Methods of treatment and maintenance therapy for bladder cancer using gemcitabine

ABSTRACT

Provided are methods of treating urothelial carcinomas of the lower tract comprising administering comprising administering gemcitabine continuously and locally to the bladder of an individual in an induction therapy and/or maintenance therapy.

RELATED APPLICATIONS

This application claims priority benefit to U.S. Provisional Application62/583,394, filed on Nov. 8, 2017, which is incorporated by reference inits entirety for all purposes.

BACKGROUND OF THE INVENTION

Bladder cancer is a significant medical problem, and currently availabletreatment options are unsatisfactory for a number of reasons. Ingeneral, bladder cancers are classified as muscle invasive bladdercancer (MIBC) or non-muscle invasive bladder cancer (NMIBC). Thepathological classification and staging of bladder cancer is as follows:pTa (urothelial involvement); pTis (high risk urothelial confined); pT1(lamina propria invasion); pT2 (muscularis invasion); pT3 (perivesicalfat invasion); and pT4 (pelvic organ extension). Bladder cancers canalso be classified by grade as Grade 1/3 (well differentiated); Grade2/3 (moderately differentiated); Grade 3/3 (poorly differentiated). Inaddition, bladder cancers can be classified by stage as Stages 0-IV(designating the extent the cancer invades the bladder wall, with Stage0 restricted to the urothelium and Stage IV describing cancer that haspenetrated the full thickness of the bladder wall invading adjacentorgans or tissues). Most bladder cancers are transitional cellcarcinomas of epithelial origin and classified as non-muscle invasivecancer (NMIBC) confined to the inner lining of the bladder. At initialpresentation, most bladder cancers are superficial NMIBCs and includestages pTa, pTis and pT1 disease. MIBC include stages pT2, pT3 and pT4.

For patients with locally advanced muscle-invasive bladder cancer(MIBC), radical cystectomy is the standard treatment, with chemotherapyadministered either before surgery or after surgery (American CancerSociety, 2016b). The National Comprehensive Cancer Network (NCCN) andthe European Association of Urology (EAU) have also recommended RC,along with radiotherapy and chemotherapy (if possible) as potentialcurative, primary treatments for patients with MIBC (NCCN, 2017; Gakis,2013). For patients who are not candidates for potentially curativetreatments, palliative radiotherapy alone or transurethral resection ofbladder tumors (TURBT) alone is recommended.

Patients who are unfit for definitive treatment with curative intentundergo repetitive or debulking, palliative TURBT to attempt to limitlocal advancement of untreated and undertreated disease. Thesenon-curative strategies are also employed to attempt to mitigate theworsening of morbid symptoms caused by invasive tumors which ofteninclude bleeding, obstruction and pain often resulting in repeatedemergency treatments.

Published Applications US2012/0203203, US2013/0158675, US2015/0360012,US2015/0165177, US2015/0165178, US2016/0199544, WO2014/145638,WO2015/200752, WO2011/031855 are hereby incorporated by reference intheir entirety. All other references disclosed herein are incorporatedby reference in their entirety.

BRIEF SUMMARY OF THE INVENTION

In some embodiments, provided herein is a method of providingmaintenance therapy for an individual, wherein the maintenance therapyfollows at least one previous therapy, wherein the maintenance therapycomprises administering gemcitabine continuously to the individual one,two or more times during one, two or more delivery periods wherein thegemcitabine is delivered locally to the bladder of the individual,wherein each delivery period is at least one week, wherein there is arest period between each delivery period of at least one week (e.g., atleast one month), and wherein the individual has a urothelial carcinomaof the lower tract.

In some embodiments, provided herein is a method of treating aurothelial carcinoma of the lower tract in an individual comprising a)administering to the individual continuously an effective amount ofgemcitabine during an induction phase; and b) administering to theindividual continuously an effective amount of gemcitabine during amaintenance phase, wherein the gemcitabine is delivered locally to thebladder of the individual, wherein the induction phase and maintenancephases are separated by a rest period, and wherein the induction phaseis about 12 weeks.

Also provided herein is a method of bladder preservation in anindividual comprising a) administering to the individual continuously aneffective amount of gemcitabine during an induction phase; and b)administering to the individual continuously an effective amount ofgemcitabine during a maintenance phase, wherein the gemcitabine isdelivered locally to the bladder of the individual, wherein theinduction phase and maintenance phases are separated by a rest period,wherein the induction phase is about 12 weeks, and wherein theindividual has a urothelial carcinoma of the lower tract.

In some embodiments, the gemcitabine is delivered into the bladder by anintravesicular device. In some embodiments, the intravesicular devicecontains about 225 mg gemcitabine.

In some embodiments, the delivery periods are each 3 weeks. In someembodiments, the rest period is about 0-3 months (e.g., 3 months).

In some embodiments, gemcitabine is delivered at a dose from about 1mg/day to about 300 mg/day during the delivery periods. In someembodiments, the concentration of gemcitabine in the urine is from about1 μg/mL to about 90 μg/mL during the delivery periods. In someembodiments, the average concentration of gemcitabine in the urine isabout 5 to 20 μg/mL during the delivery periods.

In some embodiments, the individual is ineligible for or has refusedcisplatin-based chemotherapy.

In some embodiments, the individual is unfit for, ineligible for, or hasrefused a radical cystectomy.

In some embodiments, the individual has muscle invasive bladder cancer.

In some embodiments, the individual has non-muscle invasive bladdercancer.

In some embodiments, the rest period between the induction phase and themaintenance phase is about 1-3 months.

In some embodiments, the maintenance phase comprises two or moregemcitabine delivery periods. In some embodiments, gemcitabine deliveryperiods during maintenance phase (also referred to as “the maintenancephase gemcitabine delivery periods”) are each separated by a rest periodof about 1-3 months.

In some embodiments, the maintenance phase gemcitabine delivery periodsare each 1-3 weeks.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates the study protocol as described in Example 1.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are methods of treating urothelial carcinomas of thelower tract comprising administering gemcitabine locally to the bladdera maintenance therapy. Also provided herein are methods of treatingurothelial carcinomas of the lower tract comprising administeringgemcitabine locally to the bladder an effective amount of gemcitabineduring an induction phase and/or an effective amount of gemcitabineduring an maintenance phase. In some embodiments, the induction phasecomprises more than one delivery periods, such as about two, three,four, five or more delivery periods. In some embodiments, the deliveryperiods during the induction phase are consecutive. In some embodiments,no rest period or minimum rest period (such as a rest period less than aweek) is between the consecutive delivery periods during the inductionphase. In some embodiments, the induction phase comprises about fourdelivery period (e.g., four consecutive delivery periods), wherein eachdelivery period is about 3 weeks (such as 18-24 days). In someembodiments, the maintenance phase comprises one or more deliveryperiod. In some embodiments, each delivery period during the maintenanceperiod is about three weeks (such as about 18-24 days). In someembodiments, there is a rest period between delivery periods duringmaintenance phase is about two months (e.g., about 65-75 days). In someembodiments, the urothelial carcinoma is a bladder cancer. In someembodiments, the bladder cancer is muscle-invasive bladder cancer. Insome embodiments, the bladder cancer is an organ-confinedmuscle-invasive bladder cancer (such as non-metastatic MIBC (i.e., M0MIBC), such as M0 N0 MIBC). In some embodiments, the bladder cancer is aT2 or T3 bladder cancer. In some embodiments, the bladder cancer isabout T2 or T3 M0 bladder cancer (such as T2 or T3 M0 N0 MIBC).

While radical cystectomy (RC) remains the standard treatment for MIBC(such as organ-confined (OC) MIBC), the natural history of patientsunable to receive curative intent therapy (CIT) is not well understood.Inability to receive CIT is typically due to a patient's underlyingcomorbidities, frailty, and/or age. Although a substantial proportion ofthese patients are diagnosed with clinical stage T2-T3 M0 (OC) disease,they do not receive CIT and ultimately die of their disease. In ananalysis of patients who were diagnosed with T2-T4 MIBC between 1997 and2014 in Sweden and did not receive a curative intent therapy (such asradical cystectomy), it was found that this patient populationexperienced a substantial disease-specific morbidity, were hospitalizedfrequently over their final year of life, and died primarily frombladder cancer progression. The present application provides methods fortreating urothelial carcinomas of the lower tract (such as bladdercancer, such as MIBC, such as organ-confined MIBC) that have shownadvantageous effects on patients, especially the patient population thatis unfit for, is ineligible, or unwilling to receive a curative intenttherapy such as radical cystectomy. For example, the present applicationdemonstrates that frail patients such as older patients who are unfit,ineligible or unwilling to receive radical cystectomy can well toleratean induction therapy that comprises four consecutive delivery periods ofgemcitabine and each delivery period is about 3 weeks (such as 18-24days). The present application shows that these patients have achieved50% complete response and 80% objective response rate on a per protocolbasis. It is also demonstrated that the provided methods are able toeffectively improve symptoms associated with the bladder cancer and/orprevious or present treatment of bladder cancer, such as reducingfrequencies of hematuria, alleviating pain, etc. Most strikingly, it isshown that the provided methods exhibit a durable effect for at leastabout 100 days after the induction therapy, thus providing a basis foreffective maintenance therapy as discussed herein.

I. Methods of the Present Invention

Provided herein are methods of treating a ureothial carcinoma of thelower tract by administering gemcitabine locally to the bladder multipletimes over a period of several months. Such methods are useful asmaintenance therapy, for example to prevent recurrence, and in bladdersparing protocols.

The term “continuous” or “continuously” as used herein refers tosustained administration of gemcitabine over a period of time.

The term “individual” as used herein refers to a mammal, includinghumans. An individual includes, but is not limited to, human, bovine,horse, feline, canine, rodent, or primate. In some embodiments, theindividual is human.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, “about 21 days” includes 21 days.

The term “about X-Y” used herein has the same meaning as “about X toabout Y.”

The term “effective amount” used herein refers to an amount of acompound or composition sufficient to treat a specified disorder,condition or disease such as ameliorate, palliate, lessen, and/or delayone or more of its symptoms. In reference to cancers or other unwantedcell proliferation, an effective amount comprises an amount sufficientto cause a tumor to shrink and/or to decrease the growth rate of thetumor (such as to suppress tumor growth) or to prevent or delay otherunwanted cell proliferation. In some embodiments, an effective amount isan amount sufficient to delay development. In some embodiments, aneffective amount is an amount sufficient to prevent or delay occurrenceand/or recurrence. An effective amount can be administered in one ormore administrations, in the case of cancer, the effective amount of thedrug or composition may: (i) reduce the number of cancer cells; (ii)reduce tumor size; (iii) inhibit, retard, slow to some extent andpreferably stop cancer cell infiltration into peripheral organs; (iv)inhibit (i.e., slow to some extent and preferably stop) tumormetastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrenceand/or recurrence of tumor; and/or (vii) relieve to some extent one ormore of the symptoms associated with the cancer.

In some embodiments, the methods provided herein are useful forimproving the quality of life of a patient. For example, the methodsprovided herein can be used to provide chronic treatment for patientswho are unable to undergo cystectomy. In some embodiments, the methodsprovided herein can be used as a palliative care. In some embodiments,provided herein is a method of reducing pain in an individual havingcancer.

Dosage Regimens

The following section describes various aspects (embodiments) of dosingand treatment regions, any and all of which apply to the methodsdescribed herein.

In some embodiments, provided herein is a method of maintenance therapyfollowing at least one previous therapy for an individual, comprisingadministering gemcitabine continuously and locally to the bladder of theindividual during a delivery period. In some embodiments, providedherein is a method of providing maintenance therapy for an individual,wherein the maintenance therapy follows at least one previous therapy,wherein the maintenance therapy comprises administering gemcitabinecontinuously to the individual two or more times during two or moredelivery periods, wherein the each delivery period is separated by arest period of about or at least about 1 month. In some embodiments, therest period is about or at least about 1 to 12 months, for example, atleast about 1 month, about 2 months, about 3 months, about 4 months,about 5 months, about 6 months or about one year. In some embodiments,the rest period is about 3 months. In some embodiments, the rest periodis about 65-75 days, for example, 68 to 72 days. In some embodiments,provided herein is a method of maintenance therapy following at leastone previous therapy for an individual, comprising administeringgemcitabine continuously and locally to the bladder of the individualtwo or more times during two or more consecutive delivery periods. Insome embodiments, there is a rest period of about 0-12 months after thetwo or more consecutive delivery period. In some embodiments, there is arest period of about 0-12 months after the two or more consecutivedelivery period. In some embodiments, the individual has a cT2 or cT3bladder cancer (such as cT2 or cT3 MIBC). In some embodiments, theindividual has an organ-confined muscle-invasive bladder cancer (such asnon-metastatic MIBC (i.e., M0 MIBC), such as M0 N0 MIBC). In someembodiments, the individual has a cT2 or cT3 M0 MIBC (e.g., cT2 or cT3N0 M0 MIBC). In some embodiments, the individual is responsive (such ashaving a complete response, partial response and/or stable disease) tothe at least one previous therapy, wherein the at least one previoustherapy comprises administering gemcitabine continuously and/or locally(e.g., to the bladder of the individual) to the individual. In someembodiments, there is a rest period between the previous therapy and themaintenance therapy. In some embodiments, the rest period between theprevious therapy and the maintenance therapy is about or at least about1 to 12 months, for example, at least about 1 month, about 2 months,about 3 months, about 4 months, about 5 months, about 6 months or aboutone year. In some embodiments, the rest period between the previoustherapy and the maintenance therapy is about or at least about 3 months.In some embodiments, the individual is responsive (e.g., having acomplete response, partial response, and/or stable disease) to the atleast one previous therapy. In some embodiments, the individual isselected for maintenance therapy when the individual has a completeresponse to the at least one previous therapy. In some embodiments, theprevious response comprises at least one induction phase therapycomprising administering gemcitabine continuously and locally to thebladder of the individual for at least a week (e.g., 12 weeks).

In some embodiments, provided herein is a method of providingmaintenance therapy for an individual, wherein the maintenance therapyfollows at least one previous therapy, wherein the maintenance therapycomprises administering gemcitabine continuously to the individual twoor more times during two or more delivery periods, wherein each deliveryperiod is separated by a rest period of at least 1 month, and whereineach delivery period is at least 1 week. In some embodiments, eachdelivery period is about 1 week, 2 weeks, or 3 weeks. In someembodiments, each delivery period is about 3 weeks (such as 18-24 days).In some embodiments, the individual has a cT2 or cT3 bladder cancer(such as cT2 or cT3 MIBC). In some embodiments, the individual has anorgan-confined muscle-invasive bladder cancer (such as non-metastaticMIBC (i.e., M0 MIBC), such as M0 N0 MIBC). In some embodiments, theindividual has a cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). Insome embodiments, the individual is responsive (such as having acomplete response, partial response and/or stable disease) to the atleast one previous therapy, wherein the at least one previous therapycomprises administering gemcitabine continuously and/or locally to theindividual (e.g., to the bladder of the individual). In someembodiments, the individual is responsive (e.g., having a completeresponse, partial response, and/or stable disease) to the at least oneprevious therapy. In some embodiments, the individual is selected formaintenance therapy when the individual has a complete response to theat least one previous therapy. In some embodiments, the previousresponse comprises at least one induction phase therapy comprisingadministering gemcitabine continuously and locally to the bladder of theindividual for at least a week (e.g., 12 weeks).

In some embodiments, provided herein is a method of providingmaintenance therapy for an individual, wherein the maintenance therapyfollows at least one previous therapy, wherein the maintenance therapycomprises administering gemcitabine continuously to the individual twoor more times during two or more delivery periods, wherein the eachdelivery period is separated by a rest period of at least 1 month, andwherein each delivery period is at least 1 week, and wherein thegemcitabine is delivered locally to the bladder by an intravesiculardevice. In some embodiments the device comprises about 225 mggemcitabine. In some embodiments, the delivery periods are separated bya rest period of about 2 months, about 3 months, about 4 months, about 5months, or about 6 months. In some embodiments, the rest period is about3 months. In some embodiments, the individual has a cT2 or cT3 bladdercancer (such as cT2 or cT3 MIBC). In some embodiments, the individualhas an organ-confined muscle-invasive bladder cancer (such asnon-metastatic MIBC (i.e., M0 MIBC), such as M0 N0 MIBC). In someembodiments, the individual has a cT2 or cT3 M0 MIBC (e.g., cT2 or cT3N0 M0 MIBC). In some embodiments, the individual is responsive (such ashaving a complete response, partial response and/or stable disease) tothe at least one previous therapy, wherein the at least one previoustherapy comprises administering gemcitabine continuously and/or locallyto the individual (e.g., to the bladder of the individual). In someembodiments, the individual is responsive (e.g., having a completeresponse, partial response, and/or stable disease) to the at least oneprevious therapy. In some embodiments, the individual is selected formaintenance therapy when the individual has a complete response to theat least one previous therapy. In some embodiments, the previousresponse comprises at least one induction phase therapy comprisingadministering gemcitabine continuously and locally to the bladder of theindividual for at least a week (e.g., 12 weeks).

In some embodiments, the maintenance therapy comprises administeringabout 225 mg of gemcitabine about every 3 months twice. In someembodiments, the method comprises administering about 225 mg ofgemcitabine about every 3 months 3 times, 4 times, 5 times, 6 times, 7times, or for the lifetime of the individual. In some embodiments, theindividual has a cT2 or cT3 bladder cancer (such as cT2 or cT3 MIBC). Insome embodiments, the individual has an organ-confined muscle-invasivebladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), such as M0N0 MIBC). In some embodiments, the individual has a cT2 or cT3 M0 MIBC(e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the individual isresponsive (such as having a complete response, partial response and/orstable disease) to a previous therapy, wherein the previous therapycomprises administering gemcitabine continuously and/or locally to theindividual (e.g., to the bladder of the individual).

In some embodiments, the maintenance therapy comprises administeringabout 225 mg of gemcitabine to an individual about every 2 months forabout 1 year, wherein the gemcitabine is delivered locally to thebladder. In some embodiments, about 225 mg of gemcitabine isadministered to an individual about every 3 months for about 1 year. Insome embodiments, about 225 mg of gemcitabine is administered to theindividual about every 4 months for about 1 year. In some embodimentsabout 225 mg of gemcitabine is administered to the individual aboutevery 5 months for about 1 year. In some embodiments about 225 mg ofgemcitabine is administered to the individual every 6 months. In someembodiments, the individual has muscle invasive bladder cancer. In someembodiments, the individual has non-muscle invasive bladder cancer. Insome embodiments, the individual is ineligible or has refused cisplatinbased chemotherapy. In some embodiments, the individual is unfit for, isineligible, or has refused a radical cystectomy. In some embodiments,the individual has a cT2 or cT3 bladder cancer (such as cT2 or cT3MIBC). In some embodiments, the individual has an organ-confinedmuscle-invasive bladder cancer (such as non-metastatic MIBC (i.e., M0MIBC), such as M0 N0 MIBC). In some embodiments, the individual has acT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments,the individual is responsive (such as having a complete response,partial response and/or stable disease) to a previous therapy, whereinthe previous therapy comprises administering gemcitabine continuouslyand/or locally to the individual (e.g., to the bladder of theindividual).

In some embodiments, a gemcitabine releasing device comprising about 225mg gemcitabine is placed into the bladder of an individual for at least1 week about every 3 months for about 1 year. In some embodiments agemcitabine releasing device comprising about 225 mg gemcitabine isplaced into the bladder of an individual for 2 weeks about every 3months for about 1 year. In some embodiments the gemcitabine releasingdevice comprising about 225 mg gemcitabine is placed into the bladder ofan individual for 3 weeks about every 3 months for about 1 year. In someembodiments a gemcitabine releasing device comprising about 225 mggemcitabine is placed into the bladder of an individual for 3 weeksabout every 3 months for the lifetime of the individual. In someembodiments, the individual has a cT2 or cT3 bladder cancer (such as cT2or cT3 MIBC). In some embodiments, the individual has an organ-confinedmuscle-invasive bladder cancer (such as non-metastatic MIBC (i.e., M0MIBC), such as M0 N0 MIBC). In some embodiments, the individual has acT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments,the individual is responsive (such as having a complete response,partial response and/or stable disease) to a previous therapy, whereinthe previous therapy comprises administering gemcitabine continuouslyand/or locally to the individual (e.g., to the bladder of theindividual).

In some embodiments, the method comprises (i) placing a firstgemcitabine releasing intravesicular (intravesical) device into thebladder of the individual, wherein the first gemcitabine releasingintravesicular (intravesical) device remains in the bladder, wherein thefirst gemcitabine releasing intravesicular (intravesical) devicecontains about 225 mg of gemcitabine, (ii) removing the firstgemcitabine releasing intravesicular (intravesical) device after about 3weeks (such as 18-24 days), (iii) placing a second gemcitabine releasingdevice into the bladder of the individual about 3 months after the firstgemcitabine releasing intravesicular (intravesical) device is placed inthe bladder, wherein the second gemcitabine releasing intravesicular(intravesical) device remains in the bladder for 3 weeks, wherein thesecond gemcitabine releasing intravesicular (intravesical) devicecontains about 225 mg gemcitabine, (iv) removing the second gemcitabinereleasing device. In some embodiments, steps i-iv are repeated aboutevery 3 months for about 1 year, 2 years, 3 years, or for the lifetimeof the individual. In some embodiments, the individual has muscleinvasive bladder cancer. In some embodiments, the individual hasnon-muscle invasive bladder cancer. In some embodiments, the individualis ineligible for or has refused cisplatin based chemotherapy. In someembodiments, the individual is unfit for, is ineligible, or has refuseda radical cystectomy. In some embodiments, the individual has a cT2 orcT3 bladder cancer (such as cT2 or cT3 MIBC). In some embodiments, theindividual has an organ-confined muscle-invasive bladder cancer (such asnon-metastatic MIBC (i.e., M0 MIBC), such as M0 N0 MIBC). In someembodiments, the individual has a cT2 or cT3 M0 MIBC (e.g., cT2 or cT3N0 M0 MIBC). In some embodiments, the individual is responsive (such ashaving a complete response, partial response and/or stable disease) to aprevious therapy, wherein the previous therapy comprises administeringgemcitabine continuously and/or locally to the individual (e.g., to thebladder of the individual).

In some embodiments, provided herein is a method of providingmaintenance therapy for an individual, wherein the maintenance therapyfollows at least one previous therapy, wherein the maintenance therapycomprises administering gemcitabine continuously to the individual twoor more times during two or more delivery periods wherein thegemcitabine is delivered locally to the bladder of the individual,wherein each delivery period is at least one week and wherein thegemcitabine is delivered at a dose of about 15 mg/day to 100 mg/dayduring the delivery periods. In some embodiments, the gemcitabine isdelivered at a dose of about 5 mg/day to about 250 mg/day, about 10mg/day to about 200 mg/day, about 15 mg/day to about 100 mg/day, orabout 15 mg/day to about 50 mg/day. In some embodiments, the gemcitabineis delivered at a dose of about 1 mg/day, about 5 mg/day, about 10mg/day, about 15 mg/day, about 20 mg/day, about 23 mg/day, about 25mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45mg/day, about 50 mg/day, about 55 mg/day, about 60 mg/day, about 75mg/day, about 100 mg/day, about 125 mg/day, about 150 mg/day, about 200mg/day, about 250 mg/day, or about 300 mg/day. In some embodiments, therest period is about 3 months. In some embodiments, the individual isresponsive (such as having a complete response, partial response and/orstable disease) to the at least one previous therapy, wherein the atleast one previous therapy comprises administering gemcitabinecontinuously and/or locally to the individual (e.g., to the bladder ofthe individual). In some embodiments, the individual is responsive(e.g., having a complete response, partial response, and/or stabledisease) to the at least one previous therapy. In some embodiments, theindividual is selected for maintenance therapy when the individual has acomplete response to the at least one previous therapy. In someembodiments, the previous response comprises at least one inductionphase therapy comprising administering gemcitabine continuously andlocally to the bladder of the individual for at least a week (e.g., 12weeks).

In some embodiments, provided herein is a method of providingmaintenance therapy for an individual, wherein the maintenance therapyfollows at least one previous therapy, wherein the maintenance therapycomprises administering gemcitabine continuously to the individual twoor more times during two or more delivery periods wherein thegemcitabine is delivered locally to the bladder of the individual,wherein each delivery period is at least one week and wherein theconcentration of gemcitabine in the urine of the individual is fromabout 1 μg/mL to about 10 μg/mL during the delivery periods. In someembodiments, the concentration of gemcitabine in the urine during thedelivery periods is from about 1.0 μg/mL to about 100 μg/mL, from about5.0 μg/mL to about 90 μg/mL, from about 10 μg/mL to about 80 μg/mL, fromabout 20 μg/mL to about 70 μg/mL, or from about 30 μg/mL to about 50μg/mL. In some embodiments, the concentration of gemcitabine in theurine is about 1.0 μg/mL, about 5 μg/mL, about 10 μg/mL, about 15 μg/mL,about 20 μg/mL, about 25 μg/mL, about 30 μg/mL, about 40 μg/mL, about 50μg/mL, about 60 μg/mL, about 70 μg/mL, about 80 μg/mL, about 90 μg/mL,or about 100 μg/mL. In some embodiments, the rest period is about 3months. In some embodiments, the individual has a cT2 or cT3 bladdercancer (such as cT2 or cT3 MIBC). In some embodiments, the individualhas an organ-confined muscle-invasive bladder cancer (such asnon-metastatic MIBC (i.e., M0 MIBC), such as M0 N0 MIBC). In someembodiments, the individual has a cT2 or cT3 M0 MIBC (e.g., cT2 or cT3N0 M0 MIBC). In some embodiments, the rest period is about 3 months. Insome embodiments, the individual is responsive (such as having acomplete response, partial response and/or stable disease) to the atleast one previous therapy, wherein the at least one previous therapycomprises administering gemcitabine continuously and/or locally to theindividual (e.g., to the bladder of the individual). In someembodiments, the individual is responsive (e.g., having a completeresponse, partial response, and/or stable disease) to the at least oneprevious therapy. In some embodiments, the individual is selected formaintenance therapy when the individual has a complete response to theat least one previous therapy. In some embodiments, the previousresponse comprises at least one induction phase therapy comprisingadministering gemcitabine continuously and locally to the bladder of theindividual for at least a week (e.g., 12 weeks).

In some embodiments, the previous therapy as described herein comprisesan induction phase therapy comprising delivering gemcitabinecontinuously and locally to the bladder of the individual for about 12week. In some embodiments, the delivery comprises four delivery periods(such as four consecutive delivery periods) and each delivery period isabout 3 weeks (such as 18-24 days). In some embodiments, theconcentration of gemcitabine in the urine of the individual is at leastabout 0.1 μg/mL (e.g. from about 0.1 μg/mL to about 90 μg/mL) during thedelivery periods for at least about one to two weeks out of three weeks.In some embodiments, the average concentration of gemcitabine in theurine is about 5 to 20 μg/mL for at least about one to two weeks out ofthree weeks. In some embodiments, about 225 mg of gemcitabine isadministered during each delivery period. In some embodiments, theprevious therapy comprises two or more induction phase therapies. Insome embodiments, the two or more induction phase therapies areconsecutive (i.e., there is no rest period between the two or moreinduction phase therapies). In some embodiments, there is a rest periodbetween the two or more induction phase therapies. In some embodiments,the rest period is about one month to a year. In some embodiments, therest period is about or at least about one, two, or three months.

In some embodiments, provided herein is a method of treating muscleinvasive bladder cancer in an individual who is unfit or not eligiblefor a cystectomy (such as radical cystectomy) comprising deliveringgemcitabine continuously and locally to the bladder of the individualfor about 12 week. In some embodiments, the individual is at least about70 years old (such as at least about 70, 75, 80, 85, or 90 years old).In some embodiments, the individual has a compromised immune system. Insome embodiments, the individual has a cT2 or cT3 organ-confined MIBC(e.g., N0 M0 MIBC). In some embodiments, the delivery comprises fourdelivery periods (such as four consecutive delivery periods) and eachdelivery period is about 3 weeks (such as 18-24 days). In someembodiments, the concentration of gemcitabine in the urine of theindividual is at least about 0.1 μg/mL (e.g. from about 0.1 μg/mL toabout 90 μg/mL) during the delivery periods for at least about one totwo weeks out of three weeks. In some embodiments, the averageconcentration of gemcitabine in the urine is about 5 to 20 μg/mL for atleast about one to two weeks out of three weeks. In some embodiments,about 225 mg of gemcitabine is administered during each delivery period.In some embodiments, the method further comprises a maintenance therapythat follows the delivery of gemcitabine for about 12 weeks. In someembodiments, there is a rest period between the delivery of gemcitabineand the maintenance therapy for about 12 weeks. In some embodiments, therest period is at least about one, two, or three months. In someembodiments, the maintenance therapy comprises administering gemcitabinecontinuously and locally to the bladder of the individual about or atleast about one, two or more times during one, two, or more deliveryperiods. In some embodiments, each delivery period in the maintenancephase is about or at least about one, two or three weeks. In someembodiments, the delivery period in the maintenance phase is about threeweeks and the concentration of gemcitabine in the urine of theindividual is at least about 0.1 μg/mL (e.g. from about 0.1 μg/mL toabout 90 μg/mL) during the delivery periods for at least about one totwo weeks out of three weeks. In some embodiments, about 225 mg ofgemcitabine is administered during each delivery period during themaintenance phase.

In some embodiments, provided herein is a method of treating muscleinvasive bladder cancer in an individual who is unfit or not eligiblefor a cystectomy (such as radical cystectomy) comprising at least two ormore induction phase therapy, wherein each induction phase therapycomprises delivering gemcitabine continuously and locally to the bladderof the individual for about 12 week. In some embodiments, the individualis responsive to the first induction phase therapy, such as has acomplete response, a partial response or stable disease. In someembodiments, the individual has a partial response or stable diseaseduring or after the first or a prior induction phase therapy. In someembodiments, the individual is selected for the second induction phasetherapy when the individual has a partial response or stable disease tothe first or a prior induction phase therapy. In some embodiments, theindividual is at least about 70 years old (such as at least about 70,75, 80, 85, or 90 years old). In some embodiments, the individual has acompromised immune system. In some embodiments, the individual has a cT2or cT3 organ-confined MIBC (e.g., N0 M0 MIBC). In some embodiments, thedelivery comprises four delivery periods (such as four consecutivedelivery periods) and each delivery period is about 3 weeks (such as18-24 days). In some embodiments, the concentration of gemcitabine inthe urine of the individual is at least about 0.1 μg/mL (e.g. from about0.1 μg/mL to about 90 μg/mL) during the delivery periods for at leastabout one to two weeks out of three weeks. In some embodiments, theaverage concentration of gemcitabine in the urine is about 5 to 20 μg/mLfor at least about one to two weeks out of three weeks. In someembodiments, about 225 mg of gemcitabine is administered during eachdelivery period. In some embodiments, the method further comprises amaintenance therapy that follows the delivery of gemcitabine for about12 weeks. In some embodiments, there is a rest period between thedelivery of gemcitabine and the maintenance therapy for about 12 weeks.In some embodiments, the rest period is at least about one, two, orthree months. In some embodiments, the maintenance therapy comprisesadministering gemcitabine continuously and locally to the bladder of theindividual about or at least about one, two or more times during one,two, or more delivery periods. In some embodiments, each delivery periodin the maintenance phase is about or at least about one, two or threeweeks. In some embodiments, the delivery period in the maintenance phaseis about three weeks and the concentration of gemcitabine in the urineof the individual is at least about 0.1 μg/mL (e.g. from about 0.1 μg/mLto about 90 μg/mL) during the delivery periods for at least about one totwo weeks out of three weeks. In some embodiments, about 225 mg ofgemcitabine is administered during each delivery period during themaintenance phase.

In some embodiments, provided herein is a method of treating muscleinvasive bladder cancer in an individual (such as an individual who isunfit or not eligible for a cystectomy (such as radical cystectomy))comprising at least two or more induction phase therapies and at leastone maintenance therapy, wherein each induction phase therapy comprisesdelivering gemcitabine continuously and locally to the bladder of theindividual for about 12 week. In some embodiments, the two or moreinduction phase therapies are separated by a maintenance therapy. Insome embodiments, provided herein is a method of treating muscleinvasive bladder cancer in an individual (e.g., an individual who isunfit or not eligible for a cystectomy (such as radical cystectomy))comprising delivering gemcitabine continuously and locally to thebladder of the individual for about 12 week (for example, the deliverycomprises four consecutive delivery periods and each delivery period isabout 3 weeks), wherein the individual has previously received aninduction phase therapy and a maintenance therapy (such as any of themaintenance therapy described herein). In some embodiments, theinduction phase therapy comprises four delivery periods (such as fourconsecutive delivery periods) and each delivery period is about 3 weeks(such as 18-24 days). In some embodiments, the concentration ofgemcitabine in the urine of the individual is at least about 0.1 μg/mL(e.g. from about 0.1 μg/mL to about 90 μg/mL) during the deliveryperiods for at least about one to two weeks out of three weeks. In someembodiments, the average concentration of gemcitabine in the urine isabout 5 to 20 μg/mL for at least about one to two weeks out of threeweeks. In some embodiments, about 225 mg of gemcitabine is administeredduring each delivery period. In some embodiments, the at least onemaintenance therapy comprises administering gemcitabine continuously andlocally to the bladder of the individual about or at least about one,two or more times during one, two, or more delivery periods. In someembodiments, each delivery period in the maintenance phase is about orat least about one, two or three weeks. In some embodiments, there is arest period (such as at least about 1, 2, 3, 4, 5, 6, 9, or 12 months)between two or more delivery period. In some embodiments, the deliveryperiod in the at least one maintenance phase is about three weeks andthe concentration of gemcitabine in the urine of the individual is atleast about 0.1 μg/mL (e.g. from about 0.1 μg/mL to about 90 μg/mL)during the delivery periods for at least about one to two weeks out ofthree weeks. In some embodiments, about 225 mg of gemcitabine isadministered during each delivery period during the maintenance phase.

In some embodiments, provided herein is a method of bladder preservationin an individual comprising delivering gemcitabine continuously andlocally to the bladder of the individual for about 12 week. In someembodiments, the individual is at least about 70 years old (such as atleast about 70, 75, 80, 85, or 90 years old). In some embodiments, theindividual has a compromised immune system. In some embodiments, theindividual has a cT2 or cT3 organ-confined MIBC (e.g., N0 M0 MIBC). Insome embodiments, the delivery comprises four delivery periods (such asfour consecutive delivery periods) and each delivery period is about 3weeks (such as 18-24 days). In some embodiments, the concentration ofgemcitabine in the urine of the individual is at least about 0.1 μg/mL(e.g. from about 0.1 μg/mL to about 90 μg/mL) during the deliveryperiods for at least about one to two weeks out of three weeks. In someembodiments, the average concentration of gemcitabine in the urine isabout 5 to 20 μg/mL for at least about one to two weeks out of threeweeks. In some embodiments, about 225 mg of gemcitabine is administeredduring each delivery period. In some embodiments, the method furthercomprises a maintenance therapy that follows the delivery of gemcitabinefor about 12 weeks. In some embodiments, there is a rest period betweenthe delivery of gemcitabine and the maintenance therapy for about 12weeks. In some embodiments, the rest period is at least about one, two,or three months. In some embodiments, the maintenance therapy comprisesadministering gemcitabine continuously and locally to the bladder of theindividual about or at least about one, two or more times during one,two, or more delivery periods. In some embodiments, each delivery periodin the maintenance phase is about or at least about one, two or threeweeks. In some embodiments, the delivery period in the maintenance phaseis about three weeks and the concentration of gemcitabine in the urineof the individual is at least about 0.1 μg/mL (e.g. from about 0.1 μg/mLto about 90 μg/mL) during the delivery periods for at least about one totwo weeks out of three weeks. In some embodiments, about 225 mg ofgemcitabine is administered during each delivery period during themaintenance phase.

In some embodiments, provided herein is a method of alleviating asymptom of bladder cancer in an individual comprising deliveringgemcitabine continuously and locally to the bladder of the individualfor about 12 week. In some embodiments, alleviating a symptom comprisesreducing incidences of obstruction. In some embodiments, alleviating asymptom comprises reducing frequency and or extent of hematuria orbleeding in urine. In some embodiments, alleviating a symptom comprisesreducing frequency or extent of pain. In some embodiments, the symptomis alleviated for about or at least about 3 weeks, 6 weeks, 9 weeks, 12weeks, 100 days, 120 days, 150 days, 180 days or 200 days after theinitiation of the gemcitabine delivery. In some embodiments, theindividual is at least about 70 years old (such as at least about 70,75, 80, 85, or 90 years old). In some embodiments, the individual has acompromised immune system. In some embodiments, the individual has a cT2or cT3 organ-confined MIBC (e.g., N0 M0 MIBC). In some embodiments, thedelivery comprises four delivery periods (such as four consecutivedelivery periods) and each delivery period is about 3 weeks (such as18-24 days). In some embodiments, the concentration of gemcitabine inthe urine of the individual is at least about 0.1 μg/mL (e.g. from about0.1 μg/mL to about 90 μg/mL) during the delivery periods for at leastabout one to two weeks out of three weeks. In some embodiments, theaverage concentration of gemcitabine in the urine is about 5 to 20 μg/mLfor at least about one to two weeks out of three weeks. In someembodiments, about 225 mg of gemcitabine is administered during eachdelivery period. In some embodiments, the method further comprises amaintenance therapy that follows the delivery of gemcitabine for about12 weeks. In some embodiments, there is a rest period between thedelivery of gemcitabine and the maintenance therapy for about 12 weeks.In some embodiments, the rest period is at least about one, two, orthree months. In some embodiments, the maintenance therapy comprisesadministering gemcitabine continuously and locally to the bladder of theindividual about or at least about one, two or more times during one,two, or more delivery periods. In some embodiments, each delivery periodin the maintenance phase is about or at least about one, two or threeweeks. In some embodiments, the delivery period in the maintenance phaseis about three weeks and the concentration of gemcitabine in the urineof the individual is at least about 0.1 μg/mL (e.g. from about 0.1 μg/mLto about 90 μg/mL) during the delivery periods for at least about one totwo weeks out of three weeks. In some embodiments, about 225 mg ofgemcitabine is administered during each delivery period during themaintenance phase.

In some embodiments, provided herein is a method of improving lifequality of an individual having bladder cancer comprising deliveringgemcitabine continuously and locally to the bladder of the individualfor about 12 week. In some embodiments, improving life quality comprisesalleviating a symptom associated with bladder cancer, such as reducingincidences of obstruction, reducing frequency and or extent ofhematuria, reducing frequency or extent of pain, and/or reducingemergency treatments. In some embodiments, the symptom is alleviated forabout or at least about 3 weeks, 6 weeks, 9 weeks, 12 weeks, 100 days,120 days, 150 days, 180 days or 200 days after the initiation of thegemcitabine delivery. In some embodiments, the individual is at leastabout 70 years old (such as at least about 70, 75, 80, 85, or 90 yearsold). In some embodiments, the individual has a compromised immunesystem. In some embodiments, the individual has a cT2 or cT3organ-confined MIBC (e.g., N0 M0 MIBC). In some embodiments, thedelivery comprises four delivery periods (such as four consecutivedelivery periods) and each delivery period is about 3 weeks (such as18-24 days). In some embodiments, the concentration of gemcitabine inthe urine of the individual is at least about 0.1 μg/mL (e.g. from about0.1 μg/mL to about 90 μg/mL) during the delivery periods for at leastabout one to two weeks out of three weeks. In some embodiments, theaverage concentration of gemcitabine in the urine is about 5 to 20 μg/mLfor at least about one to two weeks out of three weeks. In someembodiments, about 225 mg of gemcitabine is administered during eachdelivery period. In some embodiments, the method further comprises amaintenance therapy that follows the delivery of gemcitabine for about12 weeks. In some embodiments, there is a rest period between thedelivery of gemcitabine and the maintenance therapy for about 12 weeks.In some embodiments, the rest period is at least about one, two, orthree months. In some embodiments, the maintenance therapy comprisesadministering gemcitabine continuously and locally to the bladder of theindividual about or at least about one, two or more times during one,two, or more delivery periods. In some embodiments, each delivery periodin the maintenance phase is about or at least about one, two or threeweeks. In some embodiments, the delivery period in the maintenance phaseis about three weeks and the concentration of gemcitabine in the urineof the individual is at least about 0.1 μg/mL (e.g. from about 0.1 μg/mLto about 90 μg/mL) during the delivery periods for at least about one totwo weeks out of three weeks. In some embodiments, about 225 mg ofgemcitabine is administered during each delivery period during themaintenance phase.

In some embodiments, provided herein is a method of treating aurothelial carcinoma of the lower tract in an individual having ahistory of hematuria comprises delivering gemcitabine continuously andlocally to the bladder of the individual for about 12 week. In someembodiments, hematuria comprises chronic hematuria, frank hematuria,occasional hematuria, and/or recurrent gross hematuria. In someembodiments, the individual has a reduced symptom of hematuria (such asa reduced frequency and/or extent of hematuria) after the delivery ofgemcitabine. In some embodiments, the individual has a reduced symptomof hematuria (such as a reduced frequency and/or extent of hematuria)after the delivery of gemcitabine for at least about 3 weeks, 6 weeks, 9weeks, 12 weeks, 120 days, 150 days, 180 days, or 200 days. In someembodiments, the individual is at least about 70 years old (such as atleast about 70, 75, 80, 85, or 90 years old). In some embodiments, theindividual has a compromised immune system. In some embodiments, theindividual has a cT2 or cT3 organ-confined MIBC (e.g., N0 M0 MIBC). Insome embodiments, the delivery comprises four delivery periods (such asfour consecutive delivery periods) and each delivery period is about 3weeks (such as 18-24 days). In some embodiments, the concentration ofgemcitabine in the urine of the individual is at least about 0.1 μg/mL(e.g. from about 0.1 μg/mL to about 90 μg/mL) during the deliveryperiods for at least about one to two weeks out of three weeks. In someembodiments, the average concentration of gemcitabine in the urine isabout 5 to 20 μg/mL for at least about one to two weeks out of threeweeks. In some embodiments, about 225 mg of gemcitabine is administeredduring each delivery period. In some embodiments, the method furthercomprises a maintenance therapy that follows the delivery of gemcitabinefor about 12 weeks. In some embodiments, there is a rest period betweenthe delivery of gemcitabine and the maintenance therapy for about 12weeks. In some embodiments, the rest period is at least about one, two,or three months. In some embodiments, the maintenance therapy comprisesadministering gemcitabine continuously and locally to the bladder of theindividual about or at least about one, two or more times during one,two, or more delivery periods. In some embodiments, each delivery periodin the maintenance phase is about or at least about one, two or threeweeks. In some embodiments, the delivery period in the maintenance phaseis about three weeks and the concentration of gemcitabine in the urineof the individual is at least about 0.1 μg/mL (e.g. from about 0.1 μg/mLto about 90 μg/mL) during the delivery periods for at least about one totwo weeks out of three weeks. In some embodiments, about 225 mg ofgemcitabine is administered during each delivery period during themaintenance phase.

In some embodiments, provided herein is a method of preventing theprogression of bladder cancer in an individual comprising deliveringgemcitabine continuously and locally to the bladder of the individualfor about 12 week. In some embodiments, the prevention of theprogression lasts about or at least about one, two, three, four, five,or six months. In some embodiments, the individual is at least about 70years old (such as at least about 70, 75, 80, 85, or 90 years old). Insome embodiments, the individual has a compromised immune system. Insome embodiments, the individual has a cT2 or cT3 organ-confined MIBC(e.g., N0 M0 MIBC). In some embodiments, the delivery comprises fourdelivery periods (such as four consecutive delivery periods) and eachdelivery period is about 3 weeks (such as 18-24 days). In someembodiments, the concentration of gemcitabine in the urine of theindividual is at least about 0.1 μg/mL (e.g. from about 0.1 μg/mL toabout 90 μg/mL) during the delivery periods for at least about one totwo weeks out of three weeks. In some embodiments, the averageconcentration of gemcitabine in the urine is about 5 to 20 μg/mL for atleast about one to two weeks out of three weeks. In some embodiments,about 225 mg of gemcitabine is administered during each delivery period.In some embodiments, the method further comprises a maintenance therapythat follows the delivery of gemcitabine for about 12 weeks. In someembodiments, there is a rest period between the delivery of gemcitabineand the maintenance therapy for about 12 weeks. In some embodiments, therest period is at least about one, two, or three months. In someembodiments, the maintenance therapy comprises administering gemcitabinecontinuously and locally to the bladder of the individual about or atleast about one, two or more times during one, two, or more deliveryperiods. In some embodiments, each delivery period in the maintenancephase is about or at least about one, two or three weeks. In someembodiments, the delivery period in the maintenance phase is about threeweeks and the concentration of gemcitabine in the urine of theindividual is at least about 0.1 μg/mL (e.g. from about 0.1 μg/mL toabout 90 μg/mL) during the delivery periods for at least about one totwo weeks out of three weeks. In some embodiments, about 225 mg ofgemcitabine is administered during each delivery period during themaintenance phase.

In some embodiments, the method of treating a urothelial carcinoma ofthe lower tract in an individual comprises delivering gemcitabinecontinuously and locally to the bladder of the individual for about 12week. In some embodiments, the prevention of the progression lasts aboutor at least about one, two, three, four, five, or six months. In someembodiments, the individual is at least about 70 years old (such as atleast about 70, 75, 80, 85, or 90 years old). In some embodiments, theindividual has a compromised immune system. In some embodiments, theindividual has a cT2 or cT3 organ-confined MIBC (e.g., N0 M0 MIBC). Insome embodiments, the delivery comprises four delivery periods (such asfour consecutive delivery periods) and each delivery period is about 3weeks (such as 18-24 days). In some embodiments, the concentration ofgemcitabine in the urine of the individual is at least about 0.1 μg/mL(e.g. from about 0.1 μg/mL to about 90 μg/mL) during the deliveryperiods for at least about one to two weeks out of three weeks. In someembodiments, the average concentration of gemcitabine in the urine isabout 5 to 20 μg/mL for at least about one to two weeks out of threeweeks. In some embodiments, about 225 mg of gemcitabine is administeredduring each delivery period. In some embodiments, the method furthercomprises a maintenance therapy that follows the delivery of gemcitabinefor about 12 weeks. In some embodiments, there is a rest period betweenthe delivery of gemcitabine and the maintenance therapy for about 12weeks. In some embodiments, the rest period is at least about one, two,or three months. In some embodiments, the maintenance therapy comprisesadministering gemcitabine continuously and locally to the bladder of theindividual about or at least about one, two or more times during one,two, or more delivery periods. In some embodiments, each delivery periodin the maintenance phase is about or at least about one, two or threeweeks. In some embodiments, the delivery period in the maintenance phaseis about three weeks and the concentration of gemcitabine in the urineof the individual is at least about 0.1 μg/mL (e.g. from about 0.1 μg/mLto about 90 μg/mL) during the delivery periods for at least about one totwo weeks out of three weeks. In some embodiments, about 225 mg ofgemcitabine is administered during each delivery period during themaintenance phase.

In some embodiments, there is provided a method of maintenance therapyfollowing at least one previous therapy for an individual having aurothelial carcinoma of the lower tract, comprising administeringgemcitabine continuously and locally to the bladder of the individualone, two, or more times (e.g., two or more) during one, two or more(e.g., two or more) delivery periods, wherein each delivery period is atleast one week and there is a rest period between each delivery periodof at least one month. In some embodiments, the individual is at leastabout 70 years old (such as at least about 70, 75, 80, 85, or 90 yearsold). In some embodiments, the individual has a compromised immunesystem. In some embodiments, the individual has a cT2 or cT3organ-confined MIBC (e.g., N0 M0 MIBC). In some embodiments, the atleast one previous therapy comprises delivering gemcitabine locally andcontinuously to the bladder of the individual comprising four deliveryperiods (such as four consecutive delivery periods) and each deliveryperiod is about 3 weeks (such as 18-24 days). In some embodiments, theconcentration of gemcitabine in the urine of the individual is at leastabout 0.1 μg/mL (e.g. from about 0.1 μg/mL to about 90 μg/mL) during thedelivery periods of the previous therapy for at least about one to twoweeks out of three weeks. In some embodiments, the average concentrationof gemcitabine in the urine is about 5 to 20 μg/mL for at least aboutone to two weeks out of three weeks. In some embodiments, about 225 mgof gemcitabine is administered during each delivery period. In someembodiments, there is a rest period between the previous therapy and themaintenance therapy for about 12 weeks. In some embodiments, the restperiod is at least about one, two, or three months. In some embodiments,each delivery period in the maintenance phase is about or at least aboutone, two or three weeks. In some embodiments, the delivery period in themaintenance phase is about three weeks and the concentration ofgemcitabine in the urine of the individual is at least about 0.1 μg/mL(e.g. from about 0.1 μg/mL to about 90 μg/mL) during the deliveryperiods for at least about one to two weeks out of three weeks. In someembodiments, about 225 mg of gemcitabine is administered during eachdelivery period during the maintenance phase.

In some embodiments, there is provided a method of treating a urothelialcarcinoma of the lower tract in an individual comprising a)administering to the individual an effective amount of gemcitabinecontinuously and locally to the bladder of the individual during aninduction phase of about 12 weeks; and b) administering to theindividual an effective amount of gemcitabine continuously and locallyto the bladder of the individual during a maintenance phase, wherein theinduction phase and maintenance phases are separated by a rest period.In some embodiments, the rest period is at least about 1, 2, 3, 4, 5, 6,9, or 12 months. In some embodiments, the individual is at least about70 years old (such as at least about 70, 75, 80, 85, or 90 years old).In some embodiments, the individual has a compromised immune system. Insome embodiments, the individual has a cT2 or cT3 organ-confined MIBC(e.g., N0 M0 MIBC). In some embodiments, the induction phase comprisesdelivering gemcitabine locally and continuously to the bladder of theindividual comprising four delivery periods (such as four consecutivedelivery periods) and each delivery period is about 3 weeks (such as18-24 days). In some embodiments, the concentration of gemcitabine inthe urine of the individual is at least about 0.1 μg/mL (e.g. from about0.1 μg/mL to about 90 μg/mL) during the delivery periods of theinduction phase for at least about one to two weeks out of three weeks.In some embodiments, the average concentration of gemcitabine in theurine is about 5 to 20 μg/mL for at least about one to two weeks out ofthree weeks. In some embodiments, about 225 mg of gemcitabine isadministered during each delivery period. In some embodiments, the restperiod is at least about one, two, or three months. In some embodiments,the maintenance therapy comprises administering gemcitabine continuouslyand locally to the bladder of the individual about or at least aboutone, two or more times during one, two, or more delivery periods. Insome embodiments, each delivery period in the maintenance phase is aboutor at least about one, two or three weeks. In some embodiments, thedelivery period in the maintenance phase is about three weeks and theconcentration of gemcitabine in the urine of the individual is at leastabout 0.1 μg/mL (e.g. from about 0.1 μg/mL to about 90 μg/mL) during thedelivery periods for at least about one to two weeks out of three weeks.In some embodiments, about 225 mg of gemcitabine is administered duringeach delivery period during the maintenance phase.

In some embodiments, there is provides a method of bladder preservationin an individual having a urothelial carcinoma of the lower tractcomprising: a) administering to the individual an effective amount ofgemcitabine continuously and locally to the bladder of the individualduring an induction phase of about 12 weeks; and b) administering to theindividual an effective amount of gemcitabine continuously and locallyto the bladder of the individual during a maintenance phase, wherein theinduction phase and maintenance phases are separated by a rest period.In some embodiments, the rest period is at least about 1, 2, 3, 4, 5, 6,9, or 12 months. In some embodiments, the individual is at least about70 years old (such as at least about 70, 75, 80, 85, or 90 years old).In some embodiments, the individual has a compromised immune system. Insome embodiments, the individual has a cT2 or cT3 organ-confined MIBC(e.g., N0 M0 MIBC). In some embodiments, the induction phase comprisesdelivering gemcitabine locally and continuously to the bladder of theindividual comprising four delivery periods (such as four consecutivedelivery periods) and each delivery period is about 3 weeks (such as18-24 days). In some embodiments, the concentration of gemcitabine inthe urine of the individual is at least about 0.1 μg/mL (e.g. from about0.1 μg/mL to about 90 μg/mL) during the delivery periods of theinduction phase for at least about one to two weeks out of three weeks.In some embodiments, the average concentration of gemcitabine in theurine is about 5 to 20 μg/mL for at least about one to two weeks out ofthree weeks. In some embodiments, about 225 mg of gemcitabine isadministered during each delivery period. In some embodiments, the restperiod is at least about one, two, or three months. In some embodiments,the maintenance therapy comprises administering gemcitabine continuouslyand locally to the bladder of the individual about or at least aboutone, two or more times during one, two, or more delivery periods. Insome embodiments, each delivery period in the maintenance phase is aboutor at least about one, two or three weeks. In some embodiments, thedelivery period in the maintenance phase is about three weeks and theconcentration of gemcitabine in the urine of the individual is at leastabout 0.1 μg/mL (e.g. from about 0.1 μg/mL to about 90 μg/mL) during thedelivery periods for at least about one to two weeks out of three weeks.In some embodiments, about 225 mg of gemcitabine is administered duringeach delivery period during the maintenance phase.

In some embodiments, there is provided a method of treating a urothelialcarcinoma of the lower tract (such as bladder cancer, for example, MIBC)in an individual comprising a) administering to the individual aneffective amount of gemcitabine continuously and locally to the bladderof the individual during an induction phase comprising four consecutivedelivery period, wherein each delivery period is about three weeks; andb) administering to the individual an effective amount of gemcitabinecontinuously and locally to the bladder of the individual during amaintenance phase comprising at least two or more delivery periods,wherein each delivery period is about three weeks, and wherein there isa rest period of at least about two months between the two or moredelivery periods in the maintenance phase; and wherein the inductionphase and maintenance phases are separated by a rest period of at leastabout three months. In some embodiments, there is provided a method oftreating a urothelial carcinoma of the lower tract (such as bladdercancer, for example, MIBC) in an individual comprising a) administeringto the individual an effective amount of gemcitabine continuously andlocally to the bladder of the individual during an induction phasecomprising four consecutive delivery period, wherein each deliveryperiod is about three weeks; and b) administering to the individual aneffective amount of gemcitabine continuously and locally to the bladderof the individual during a maintenance phase comprising two or moredelivery periods, wherein each delivery period is about three weeks, andwherein there is a rest period of about two months between the two ormore delivery periods in the maintenance phase; and wherein theinduction phase and maintenance phases are separated by a rest period ofabout three months. In some embodiments, the individual is at leastabout 70 years old (such as at least about 70, 75, 80, 85, or 90 yearsold). In some embodiments, the individual has a compromised immunesystem. In some embodiments, the individual has a cT2 or cT3organ-confined MIBC (e.g., N0 M0 MIBC). In some embodiments, theconcentration of gemcitabine in the urine of the individual is at leastabout 0.1 μg/mL (e.g. from about 0.1 μg/mL to about 90 μg/mL) during thedelivery periods of the induction phase and/or maintenance phase for atleast about one to two weeks out of three-week delivery period. In someembodiments, the average concentration of gemcitabine in the urine isabout 5 to 20 μg/mL for at least about one to two weeks out ofthree-week delivery period during the induction phase and/or themaintenance therapy. In some embodiments, about 225 mg of gemcitabine isadministered during each delivery period during the induction phaseand/or the maintenance therapy.

In some embodiments, the method of bladder preservation in an individualcomprises administering to the individual an effective amount ofgemcitabine, wherein the gemcitabine is delivered locally to the bladderof the individual for about 12 weeks, and wherein the individual has acT2 bladder cancer. In some embodiments, the method of bladderpreservation in an individual comprises administering to the individualan effective amount of gemcitabine, wherein the gemcitabine is deliveredlocally to the bladder during four delivery periods (such as fourconsecutive delivery periods) and each delivery period is about 3 weeks(such as 18-24 days), and wherein the individual has a cT2 bladdercancer. In some embodiments, the method of bladder preservation in anindividual comprises administering to the individual an effective amountof gemcitabine, wherein the gemcitabine is delivered locally to thebladder during four delivery periods (such as four consecutive deliveryperiods) and each delivery period is about 3 weeks (such as 18-24 days),wherein about 225 mg of gemcitabine is administered during each deliveryperiod, and wherein the individual has a cT2 bladder cancer. In someembodiments, the individual has an organ-confined muscle-invasivebladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), such as M0N0 MIBC). In some embodiments, the individual has a cT2 or cT3 M0 MIBC(e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, two adjacentdelivery periods is separated by a rest period. In some embodiments, therest period is less than or no more than about 7 days, 6 days, 5 days, 4days, 3 days, 2 days or 1 day.

In some embodiments, the method of treating a urothelial carcinoma ofthe lower tract in an individual comprises administering to theindividual an effective amount of gemcitabine, wherein the gemcitabineis delivered locally to the bladder of the individual for about 12weeks, and wherein the individual has a cT2 bladder cancer. In someembodiments, the method of treating a urothelial carcinoma of the lowertract in an individual comprises administering to the individual aneffective amount of gemcitabine, wherein the gemcitabine is deliveredlocally to the bladder during four delivery periods (such as fourconsecutive delivery periods) and each delivery period is about 3 weeks(such as 18-24 days), and wherein the individual has a cT2 bladdercancer. In some embodiments, the method of treating a urothelialcarcinoma of the lower tract in an individual comprises administering tothe individual an effective amount of gemcitabine, wherein thegemcitabine is delivered locally to the bladder during four deliveryperiods (such as four consecutive delivery periods) and each deliveryperiod is about 3 weeks (such as 18-24 days), wherein about 225 mg ofgemcitabine is administered during each delivery period, and wherein theindividual has a cT2 bladder cancer. In some embodiments, the individualhas an organ-confined muscle-invasive bladder cancer (such asnon-metastatic MIBC (i.e., M0 MIBC), such as M0 N0 MIBC). In someembodiments, the individual has a cT2 or cT3 M0 MIBC (e.g., cT2 or cT3N0 M0 MIBC). In some embodiments, two adjacent delivery periods isseparated by a rest period. In some embodiments, the rest period is lessthan or no more than about 7 days, 6 days, 5 days, 4 days, 3 days, 2days or 1 day.

In some embodiments, the methods provided herein can be used as a methodof bladder preservation in an individual. In some embodiments, themethod of bladder preservation in an individual comprises administeringto the individual an effective amount of gemcitabine during an inductionphase and administering to the individual an effective amount ofgemcitabine during a maintenance phase, wherein the gemcitabine isdelivered locally to the bladder, wherein the induction phase andmaintenance phases are separated by a rest period, and wherein theinduction phase is about 12 weeks. In some embodiments, the individualdoes not receive a radical cystectomy. In some embodiments, the restphase is about 1 month, about 2 months, about 3 months, about 4 months,about 5 months, or about 6 months. In some embodiments, the inductionphase comprises administering about 900 mg gemcitabine to theindividual. In some embodiments, the individual has non-muscle invasivebladder cancer. In some embodiments, the individual is ineligible for orhas refused cisplatin based chemotherapy. In some embodiments, theindividual has a cT2 or cT3 bladder cancer (such as cT2 or cT3 MIBC). Insome embodiments, the individual has an organ-confined muscle-invasivebladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), such as M0N0 MIBC). In some embodiments, the individual has a cT2 or cT3 M0 MIBC(e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the induction phasecomprises installing a gemcitabine releasing device every 3 weeks for atotal of 12 weeks, wherein each device releases 225 mg gemcitabine. Insome embodiments, the rest period is about 2-3 months, such as about65-75 days, such as 68-27 days. The maintenance phase comprises placinga gemcitabine releasing device in the bladder of the individualcomprising 225 mg gemcitabine every 3 months for 1 year. In someembodiments, the rest period is about 3 months. In some embodiments, theindividual is responsive (such as having a complete response, partialresponse and/or stable disease) to the induction phase therapy.

In some embodiments, the method of bladder preservation in an individualcomprises administering to the individual an effective amount ofgemcitabine during an induction phase and administering to theindividual an effective amount of gemcitabine during a maintenancephase, wherein the gemcitabine is delivered locally to the bladder,wherein the induction phase and maintenance phase are separated by arest period, and wherein the induction phase is about 12 weeks, andwherein the individual has a cT2 bladder cancer. In some embodiments,the method of bladder preservation in an individual comprisesadministering to the individual an effective amount of gemcitabineduring an induction phase and administering to the individual aneffective amount of gemcitabine during a maintenance phase, wherein thegemcitabine is delivered locally to the bladder, wherein the inductionphase comprises four delivery periods (such as four consecutive deliveryperiods) and each delivery period is about 3 weeks (such as 18-24 days),wherein the maintenance phase comprises administering gemcitabine to theindividual about every 3 months, wherein the induction phase andmaintenance phases are separated by a rest period, and wherein theindividual has a cT2 bladder cancer. In some embodiments, the method ofbladder preservation in an individual comprises administering to theindividual an effective amount of gemcitabine during an induction phaseand administering to the individual an effective amount of gemcitabineduring a maintenance phase, wherein the gemcitabine is delivered locallyto the bladder, wherein the induction phase comprises four deliveryperiods (such as four consecutive delivery periods) and each deliveryperiod is about 3 weeks (such as 18-24 days) wherein about 225 mg ofgemcitabine is administered during each delivery period, wherein themaintenance phase has a delivery period (i.e., maintenance phasedelivery period) of 3 weeks every 3 months wherein about 225 mg ofgemcitabine is administered during each maintenance phase deliveryperiod, wherein the induction phase and maintenance phases are separatedby a rest period, and wherein the individual has a cT2 bladder cancer.In some embodiments, the maintenance phase is about 1 year, 2 years, 3years, 5 year, 10 years, for the lifetime of the individual, or untildisease progression or toxicity. In some embodiments, the rest period isabout 2-3 months, such as about 65-75 days, such as 68-72 days. In someembodiments, the rest period is about 3 months. In some embodiments, theindividual is responsive (such as having a complete response, partialresponse and/or stable disease) to the induction phase therapy. In someembodiments, the individual has an organ-confined muscle-invasivebladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), such as M0N0 MIBC). In some embodiments, the individual has a cT2 or cT3 M0 MIBC(e.g., cT2 or cT3 N0 M0 MIBC).

Also provided herein is a method of treating a urothelial carcinoma ofthe lower tract in an individual comprising administering to theindividual an effective amount of gemcitabine during an induction phaseand administering to the individual an effective amount of gemcitabineduring a maintenance phase, wherein the gemcitabine is delivered locallyto the bladder, wherein the induction phase and maintenance phases areseparated by a rest period, and wherein the induction phase is about 12weeks. In some embodiments, the method of treating a urothelialcarcinoma of the lower tract in an individual comprises administering tothe individual an effective amount of gemcitabine during an inductionphase and administering to the individual an effective amount ofgemcitabine during a maintenance phase, wherein the gemcitabine isdelivered locally to the bladder, wherein the induction phase andmaintenance phases are separated by a rest period, and wherein theinduction phase is about 84 days. In some embodiments, the rest periodis 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In someembodiments, the individual has muscle invasive bladder cancer. In someembodiments, the individual has non-muscle invasive bladder cancer. Insome embodiments, the individual is ineligible for or has refusedcisplatin based chemotherapy. In some embodiments, the individual isunfit for, is ineligible, or has refused a radical cystectomy. In someembodiments, the individual has a cT2 or cT3 bladder cancer (such as cT2or cT3 MIBC). In some embodiments, the individual has an organ-confinedmuscle-invasive bladder cancer (such as non-metastatic MIBC (i.e., M0MIBC), such as M0 N0 MIBC). In some embodiments, the individual has acT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments,the rest period is about 3 months. In some embodiments, the individualis responsive (such as having a complete response, partial responseand/or stable disease) to the induction phase therapy.

Also provided herein is a method of treating a urothelial carcinoma ofthe lower tract in an individual comprising administering to theindividual an effective amount of gemcitabine during an induction phaseand administering to the individual an effective amount of gemcitabineduring a maintenance phase, wherein the gemcitabine is delivered locallyto the bladder, wherein the induction phase and maintenance phases areseparated by a rest period, wherein the induction phase is about 12weeks, and wherein the individual has a cT2 bladder cancer. Alsoprovided herein is a method of treating a urothelial carcinoma of thelower tract in an individual comprising administering to the individualan effective amount of gemcitabine during an induction phase andadministering to the individual an effective amount of gemcitabineduring a maintenance phase, wherein the gemcitabine is delivered locallyto the bladder, wherein the induction phase comprises four deliveryperiods (such as four consecutive delivery periods) and each deliveryperiod is about 3 weeks (such as 18-24 days), wherein the maintenancephase comprises administering gemcitabine to the individual about every3 months, wherein the induction phase and maintenance phases areseparated by a rest period, wherein the induction phase is about 12weeks, and wherein the individual has a cT2 bladder cancer. Alsoprovided herein is a method of treating a urothelial carcinoma of thelower tract in an individual comprising administering to the individualan effective amount of gemcitabine during an induction phase andadministering to the individual an effective amount of gemcitabineduring a maintenance phase, wherein the gemcitabine is delivered locallyto the bladder, wherein the induction phase comprises four deliveryperiods (such as four consecutive delivery periods) and each deliveryperiod is about 3 weeks (such as 18-24 days), wherein the maintenancephase comprises administering gemcitabine to the individual about every3 months, wherein the induction phase and maintenance phases areseparated by a rest period, wherein the induction phase is about 12weeks, and wherein the individual has a cT2 bladder cancer. Alsoprovided herein is a method of treating a urothelial carcinoma of thelower tract in an individual comprising administering to the individualan effective amount of gemcitabine during an induction phase andadministering to the individual an effective amount of gemcitabineduring a maintenance phase, wherein the gemcitabine is delivered locallyto the bladder, wherein the induction phase comprises four deliveryperiods (such as four consecutive delivery periods) and each deliveryperiod is about 3 weeks (such as 18-24 days), wherein the maintenancephase comprises administering gemcitabine to the individual about every3 months, wherein the induction phase comprises four delivery periods(such as four consecutive delivery periods) and each delivery period isabout 3 weeks (such as 18-24 days) wherein about 225 mg of gemcitabineis administered during each delivery period, wherein the maintenancephase has a delivery period (i.e., maintenance phase delivery period) of3 weeks every 3 months wherein about 225 mg gemcitabine is administeredduring each maintenance phase delivery period, wherein the inductionphase and maintenance phases are separated by a rest period, and whereinthe individual has a cT2 bladder cancer. In some embodiments, themaintenance phase is about 1 year, 2 years, 3 years, 5 year, 10 years,for the lifetime of the individual, or until disease progression ortoxicity. In some embodiments, the rest period is about 2-3 months, suchas about 65-75 days, such as 68-72 days. In some embodiments, the restperiod is about 3 months. In some embodiments, the individual isresponsive (such as having a complete response, partial response and/orstable disease) to the induction phase therapy. In some embodiments, theindividual has an organ-confined muscle-invasive bladder cancer (such asnon-metastatic MIBC (i.e., M0 MIBC), such as M0 N0 MIBC). In someembodiments, the individual has a cT2 or cT3 M0 MIBC (e.g., cT2 or cT3N0 M0 MIBC).

In some embodiments, the method of treating a urothelial carcinoma ofthe lower tract in an individual comprises administering to theindividual an effective amount of gemcitabine during an induction phaseand administering to the individual an effective amount of gemcitabineduring a maintenance phase, wherein the gemcitabine is delivered locallyto the bladder, wherein the induction phase and maintenance phases areseparated by a rest period, wherein the induction phase is 12 weeks andthe rest period is about 3 months. In some embodiments, the inductionphase comprises administering about 900 mg of gemcitabine to theindividual over 12 weeks. In some embodiments, the individual has muscleinvasive bladder cancer. In some embodiments, the individual hasnon-muscle invasive bladder cancer. In some embodiments, the individualis ineligible for or has refused cisplatin based chemotherapy. In someembodiments, the individual is unfit for, is ineligible for, or hasrefused a radical cystectomy. In some embodiments, the individual has acT2 or cT3 bladder cancer (such as cT2 or cT3 MIBC). In someembodiments, the individual has an organ-confined muscle-invasivebladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), such as M0N0 MIBC). In some embodiments, the individual has a cT2 or cT3 M0 MIBC(e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the rest period isabout 3 months. In some embodiments, the individual is responsive (suchas having a complete response, partial response and/or stable disease)to the induction phase therapy.

In some embodiments, the method comprises administering gemcitabine toan individual for 12 weeks, followed by a about 2-3 months rest period,followed by a maintenance phase, wherein the maintenance phase comprisesadministering gemcitabine to the individual about every 3 months for atleast one year, wherein the gemcitabine is delivered locally to thebladder. In some embodiments, the method comprises administeringgemcitabine to an individual for 12 weeks, followed by a 2-3 months restperiod, followed by a maintenance phase, wherein the gemcitabine isdelivered locally to the bladder, wherein the maintenance phasecomprises administering about 225 mg gemcitabine to individual aboutevery 3 months for about 1 year. In some embodiments, the maintenancephase is about 1 year, about 2 years, about 3 years, 5 year, 10 years,or for the lifetime of the individual. In some embodiments, themaintenance phase comprises delivering gemcitabine about every 3 months2 times, 3 times, 4 times, 5 times, 6 times, or for the lifetime of theindividual. In some embodiments, the maintenance phase delivery periodsare each about 3 weeks (such as 18-24 days). In some embodiments, themaintenance phase delivery periods are about 1 week, about 2 weeks, orabout 3 weeks. In some embodiments, the individual has muscle invasivebladder cancer. In some embodiments, the individual has non-muscleinvasive bladder cancer. In some embodiments, the individual isineligible or has refused cisplatin based chemotherapy. In someembodiments, the individual is unfit for, is ineligible, or has refuseda radical cystectomy. In some embodiments, the individual has a cT2 orcT3 bladder cancer (such as cT2 or cT3 MIBC). In some embodiments, theindividual has an organ-confined muscle-invasive bladder cancer (such asnon-metastatic MIBC (i.e., M0 MIBC), such as M0 N0 MIBC). In someembodiments, the individual has a cT2 or cT3 M0 MIBC (e.g., cT2 or cT3N0 M0 MIBC). In some embodiments, the rest period is about 3 months. Insome embodiments, the individual is responsive (such as having acomplete response, partial response and/or stable disease) to the12-week administration of gemcitabine.

In some embodiments, provided herein is a method of treating aurothelial carcinoma of the lower tract in an individual comprising aninduction phase and a maintenance phase, wherein the induction phasecomprises administering about 900 mg of gemcitabine to individual over12 weeks, wherein the maintenance phase comprises administering about225 mg of gemcitabine to the individual about every 3 months for atleast one year, wherein the gemcitabine is delivered locally to thebladder, and wherein the induction phase and the maintenance phase areseparated by a rest period of about 2-3 months. In some embodiments, theindividual has a cT2 or cT3 bladder cancer (such as cT2 or cT3 MIBC). Insome embodiments, the individual has an organ-confined muscle-invasivebladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), such as M0N0 MIBC). In some embodiments, the individual has a cT2 M0 MIBC. In someembodiments, the rest period is about 3 months. In some embodiments, theindividual is responsive (such as having a complete response, partialresponse and/or stable disease) to the induction phase therapy.

In some embodiments, provided herein is a method of treating aurothelial carcinoma of the lower tract in an individual comprising aninduction phase and a maintenance phase, wherein the induction phasecomprises administering about 900 mg of gemcitabine to individual over12 weeks, wherein the maintenance phase comprises administering about225 mg of gemcitabine to the individual about every 3 months for atleast one year, wherein the gemcitabine is delivered locally to thebladder, and wherein the induction phase and the maintenance phase areseparated by a rest period of about 2-3 months, wherein the individualhas a cT2 bladder cancer. In some embodiments, the individual has anorgan-confined muscle-invasive bladder cancer (such as non-metastaticMIBC (i.e., M0 MIBC), such as M0 N0 MIBC). In some embodiments, theindividual has a cT2 M0 MIBC. In some embodiments, provided herein is amethod of treating a urothelial carcinoma of the lower tract in anindividual comprising an induction phase and a maintenance phase,wherein the induction phase comprises administering about 900 mg ofgemcitabine to individual over 12 weeks, wherein the maintenance phasecomprises administering about 225 mg of gemcitabine to the individualabout every 3 months for at least one year, wherein the gemcitabine isdelivered locally to the bladder, and wherein the induction phase andthe maintenance phase are separated by a rest period of about 2-3months, wherein the individual has a cT3 bladder cancer. In someembodiments, the rest period is about 3 months. In some embodiments, theindividual is responsive (such as having a complete response, partialresponse and/or stable disease) to the induction phase therapy.

In some embodiments, the induction phase comprises four delivery periods(such as four consecutive delivery periods) and each delivery period isabout 3 weeks (such as 18-24 days). In some embodiments, the inductionphase comprises four delivery periods (such as four consecutive deliveryperiods) and each delivery period is about 3 weeks (such as 18-24 days)wherein about 225 mg of gemcitabine is administered during each deliveryperiod. In some embodiments, an intravesicular device comprising about225 mg of gemcitabine is inserted into the bladder every 3 weeks for 12weeks during the induction phase. In some embodiments, the individualhas muscle invasive bladder cancer. In some embodiments, the individualhas non-muscle invasive bladder cancer. In some embodiments, theindividual is ineligible or has refused cisplatin based chemotherapy. Insome embodiments, the individual is unfit for, is ineligible, or hasrefused a radical cystectomy. In some embodiments, the individual has acT2 or cT3 bladder cancer (such as cT2 or cT3 MIBC). In someembodiments, the individual has an organ-confined muscle-invasivebladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), such as M0N0 MIBC). In some embodiments, the individual has a cT2 or cT3 M0 MIBC(e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the rest period isabout 3 months. In some embodiments, the individual is responsive (suchas having a complete response, partial response and/or stable disease)to the induction phase therapy.

In some embodiments, provided herein is a method of treating aurothelial carcinoma of the lower tract of an individual comprising aninduction phase comprising four delivery periods (such as fourconsecutive delivery periods) and each delivery period is about 3 weeks(such as 18-24 days), a rest period, and a maintenance period comprising2 or more gemcitabine delivery periods separated by about 3 months,wherein each about 225 mg of gemcitabine is administered during eachdelivery period. In some embodiments, the individual has a cT2 or cT3bladder cancer (such as cT2 or cT3 MIBC). In some embodiments, theindividual has an organ-confined muscle-invasive bladder cancer (such asnon-metastatic MIBC (i.e., M0 MIBC), such as M0 N0 MIBC). In someembodiments, the individual has a cT2 or cT3 M0 MIBC (e.g., cT2 or cT3N0 M0 MIBC). In some embodiments, the rest period is about 3 months. Insome embodiments, the individual is responsive (such as having acomplete response, partial response and/or stable disease) to theinduction phase therapy.

In some embodiments, the maintenance phase is a treatment phase thatfollows at least one primary therapy. In some embodiments, the primarytherapy is an induction therapy comprising administering gemcitabine. Insome embodiments, the maintenance therapy comprises two or moregemcitabine delivery periods separated by a period of at least 1 month,wherein the delivery periods comprise administering about 225 mg ofgemcitabine, wherein the gemcitabine is delivered locally to thebladder. In some embodiments, the delivery periods of the maintenancephase are separated by about 2, about 3, about 4, about 5, or about 6months. In some embodiments, the maintenance phase comprises two or moredelivery periods separated by a period of about 3 months, wherein eachdelivery period comprises administering about 225 mg of gemcitabine tothe individual, wherein the gemcitabine is delivered locally to thebladder of the individual. In some embodiments, the maintenance phasecomprises placing a gemcitabine releasing device in the bladder of theindividual comprising about 225 mg gemcitabine, about every 3 months forabout 1 year. In some embodiments, the maintenance phase deliveryperiods are each about 1 week, about 2 weeks, or about 3 weeks. In someembodiments, the maintenance phase delivery periods are each about 3weeks (such as 18-24 days). In some embodiments, the individual hasmuscle invasive bladder cancer. In some embodiments, the individual hasnon-muscle invasive bladder cancer. In some embodiments, the individualis ineligible for or has refused cisplatin based chemotherapy. In someembodiments, the individual is unfit for, is ineligible for, or hasrefused a radical cystectomy. In some embodiments, the rest period isabout 3 months. In some embodiments, the individual is responsive (suchas having a complete response, partial response and/or stable disease)to the at least one primary therapy.

Patient Populations

The methods provided herein are useful for treatment of a range ofindividuals having urothelial carcinomas. For example in someembodiments, the urothelial carcinoma is a bladder cancer. In someembodiments, the bladder cancer is locally-advanced bladder cancer. Insome embodiments, the bladder cancer is a metastatic bladder cancer. Insome embodiments, the bladder cancer is muscle invasive bladder cancer.In some embodiments, the bladder cancer is non-muscle invasive bladdercancer. In some embodiments, bladder cancer is carcinoma in situ. Insome embodiments the bladder cancer is BCG (Bacillus Calmette-Guerin)refractory cancer. In some embodiments, the bladder cancer is papillarybladder cancer. In some embodiments, the bladder cancer is grade 1/3,2/3, or 3/3. In some embodiments, the bladder cancer is stage I, stageII, stage III, or stage IV bladder cancer. In some embodiments, thebladder cancer is high grade invasive papillary urothelial carcinoma. Insome embodiments, the bladder cancer is non-invasive high gradeurothelial carcinoma. In some embodiments, the bladder cancer ismultifocal invasive high grade papillary urothelial carcinoma. In someembodiments the bladder cancer is cT2 or cT3. In some embodiments, thebladder is cT2 with carcinoma in situ.

In some embodiments, provided herein is a method of treating bladdercancers, (for example MIBC) in an individual who is not eligible forneoadjuvant cisplatin-based therapy comprising administering gemcitabinelocally to the bladder. In some embodiments, provided herein is a methodof treating bladder cancers, (for example MIBC) in an individual whorefuses neoadjuvant cisplatin-based therapy comprising administering agemcitabine locally to the bladder. In some embodiments, provided hereinis a method of treating bladder cancers, (for example MIBC) in anindividual having cT2 disease and an absence of high-risk features suchas lymphovascular invasion (LVI), hydronephrosis, and concomitantcarcinoma in situ (CIS) comprising administering a gemcitabine locallyto the bladder. In some embodiments, provided herein is a method oftreating bladder cancers, (for example MIBC) in an individual who willreceive radical cystectomy but is ineligible for cisplatin-basedneoadjuvant therapy comprising administering gemcitabine locally to thebladder. In some of these embodiments, the individual has cT2 cancer. Insome embodiments, the individual has an organ-confined muscle-invasivebladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), such as M0N0 MIBC). In some embodiments, the individual has a cT2 M0 N0 MIBC.

In some embodiments, an individual is ineligible for cisplatin-basedtherapy based upon co-morbidities including poor performance status,poor renal function, hearing loss, peripheral neuropathy, and cardiacdisease. In some embodiments, an individual is ineligible forcisplatin-based therapy based upon the absence of one or more high-riskfeatures such as lymphovascular invasion (LVI), hydronephrosis, andconcomitant carcinoma in situ (CIS).

Accordingly, in some embodiments, provided herein is a method oftreating an individual who is ineligible for cisplatin-based therapycomprising administering gemcitabine to the individual about every 3months, wherein the gemcitabine is delivered locally to the bladder ofthe individual for at least 1 week. In some embodiments, about 225 mggemcitabine is administered about every 3 months for about 1 year, about2 years, about 4 years, or for the lifetime of the patient. In someembodiments, gemcitabine is delivered continuously for about 1 week,about 2 weeks, or about 3 weeks during the delivery periods.

In some of these embodiments, the method comprises administering about225 mg of gemcitabine to an individual for 3 weeks about every 3 monthsfor about 2 years. In some of these embodiments, the method comprisesadministering about 225 mg of gemcitabine to an individual for 3 weeksabout every 3 months for about 3 years. In some of these embodiments,the method comprises administering about 225 mg of gemcitabine anindividual for 3 weeks about every 3 months for the lifetime of theindividual. In some embodiments the method comprises a 12 week inductionphase followed by a maintenance phase.

Up until now, neoadjuvant therapy followed by radical cystectomy, orremoval of the bladder has been standard therapy for treatment of muscleinvasive bladder cancer. Individuals who are unfit for radicalcystectomy undergo palliative transurethral resection of bladder tumors(TURBT) to attempt to limit local advancement of untreated andundertreated disease. Such treatments may temporarily manage localsymptoms of hematuria, pain and urgency, but are not employed withcurative intent. Therefore, in one aspect the present invention providesa method of treating bladder cancers, (for example MIBC) in anindividual who is unfit or not eligible for a cystectomy byadministering gemcitabine locally to the bladder.

In some embodiments, provided herein is a method of treating bladdercancers, (for example MIBC) of the lower tract in an individual who isunfit for cystectomy comprising delivering gemcitabine locally to thebladder. In some embodiments, provided herein is a method of treatingbladder cancers, (for example MIBC) in an individual who is ineligiblefor cystectomy comprising delivering gemcitabine locally to the bladder.In some embodiments, provided herein is a method of treating bladdercancers, (for example MIBC) in an individual who is frail comprisingdelivering gemcitabine locally to the bladder. In some embodiments,provided herein is a method of treating bladder cancers, (for exampleMIBC) in an individual who cannot tolerate radical cystectomy comprisingdelivering gemcitabine locally to the bladder. In some embodiments,provided herein is a method of treating bladder cancers, (for exampleMIBC) in an individual without removing the bladder of the individual,comprising delivering gemcitabine locally to the bladder. In someembodiments, provided herein is a method of treating bladder cancers,(for example MIBC) in an individual, wherein the individual is unfit orineligible for a cystectomy, comprising delivering gemcitabine locallyto the bladder. In some embodiments, provided herein is a method oftreating bladder cancer (for example MIBC) in an individual, wherein thebladder cancer is metastatic bladder cancer. In some embodiments,provided herein is a method of treating bladder cancers, (for exampleMIBC) in an individual, wherein the individual has cT2-cT3 disease (suchas cT2-cT3 M0 disease), comprising delivering gemcitabine locally to thebladder.

In some embodiments, provided herein is a method of treating muscleinvasive bladder cancer in an individual who is unfit or not eligiblefor a cystectomy comprising delivering gemcitabine locally to thebladder of the individual for at least 1 week every three months. Insome of these embodiments, the gemcitabine may be delivered continuouslyto the bladder chronically, or for the lifetime of the individual toimprove the quality of life of the individual. In some embodiments,about 225 mg gemcitabine is administered about every 3 months for about1 year, about 2 years, about 4 years, or for the lifetime of thepatient. In some embodiments, gemcitabine is delivered continuously forabout 1 week, about 2 weeks, or about 3 weeks during the deliveryperiods.

In some embodiments, the individual is ineligible for or has refusedcisplatin-based chemotherapy. In some embodiments, the individual isunfit for, ineligible for or has refused a radical cystectomy.

In some embodiments, the individual is ineligible for radical cystectomyunder the National Comprehensive Cancer Network (NCCN) guidelines. Forexample, the individual may be unfit for curative therapy due tofrailty. Prior to the present methods, such individuals typicallyreceived palliative radiation without chemotherapy (3.5 Gy/fraction—10treatments; or 7 Gy/fraction—7 treatments; TURBT; or no treatment). Insome embodiments the individual is unfit for platinum-basedchemotherapy. In some embodiments, chemotherapy prior to radiationtherapy is not recommended for the individual. In some embodiments, theindividual does not receive curative therapy or systemic chemotherapy.In some embodiments, the individual has cT2-cT3 disease (such as cT2-cT3M0 disease).

In some embodiments, the individual cannot tolerate radical cystectomybased upon the American Society of Anesthesiology (ASA) guidelines. Forexample the individual who cannot tolerate radial cystectomy may bedeemed medically unfit for surgery requiring general or epiduralanesthesia.

In other embodiments, the individual may lack operative post-operativecare infrastructure or personal as determined by the ComprehensiveGeriatric Assessment provided by the American Society ofAnesthesiologists. Under these guidelines, an individual is deemed frailif he or she shows abnormal independent activities of daily living,severe malnutrition, cognitive impairment, or comorbidities cumulativeillness rating scale for geriatrics (CISR-G) grades 3-4.

The methods of the present invention also provide important andsignificant treatment benefits compared to standard therapeutic regimensthat call for removal of the bladder. The present invention also has theadvantage of being useful as a bladder sparing protocol for individualswho are eligible for a cystectomy, but elect not to have a cystectomy.The present methods result in a greatly improved quality of life forindividuals, who may be able to retain their bladder after havingbladder cancer, compared to the presently available treatments.Accordingly, in some embodiments, there is provided herein is a bladdersparing method of treating bladder cancers, (for example MIBC) in anindividual comprising delivering an gemcitabine locally to the bladder.In some embodiments, provided herein is a method of treating bladdercancers (for example MIBC) without removing the bladder of theindividual comprising delivering gemcitabine) locally to the bladder.Also provided herein is a method of treating bladder cancers (forexample MIBC), in an individual who would otherwise undergo a cystectomycomprising delivering gemcitabine locally to the bladder. In someembodiments, provided herein is a method of treating bladder cancers(for example MIBC), in an individual who is eligible for, but elects notto receive, a cystectomy, comprising delivering gemcitabine locally tothe bladder. In some embodiments, provided herein is a method of bladderpreservation as an alternative to radical cystectomy, comprisingdelivering gemcitabine locally to the bladder. In some embodiments,provided herein is a method of treating bladder cancers (for exampleMIBC), in an individual who elects not to undergo a cystectomy,comprising delivering gemcitabine locally to the bladder. In someembodiments, provided herein is a method of preserving the bladder of anindividual, comprising delivering gemcitabine locally to the bladder. Insome embodiments, provided herein is a method of treating bladdercancers (for example MIBC), in an individual, without removing thebladder, comprising delivering an an gemcitabine locally to the bladder.In some embodiments, provided herein is a method of treating a CT2urothelial carcinoma in an individual who would otherwise receive acystectomy, comprising delivering gemcitabine locally to the bladder ofthe individual.

In some embodiments, the present methods are especially suited fortreatment of individual with CT2 patients who would typically receive aradical resection followed by neoadjuvant therapy. The present methodsresult in local/regional (locoregional) control of the disease,including nodes, and thus can be used for long-term treatment in thisbladder sparing population. The present methods also result in freedomfrom invasive recurrence, good long term bladder function, and low ratesof salvage cystectomy, all of which are of major importance in theelderly, relatively frail population of individuals with bladder cancerwho have an average age of 70.

In some embodiments, the present methods are applicable to subjects thathave a history of hematuria (such as chronic hematuria, frank hematuria,recurrent gross hematuria, or recurrent hematuria). The present methodsreduce and/or control the symptom of hematuria, for as long as about 200days.

In some embodiments, the individual has muscle-invasive bladder cancer(MIBC). In some embodiments, the individual has non-muscle invasivebladder cancer (NMIBC).

In some embodiments, the individual has non-metastatic (M0) bladdercancer (e.g., MIBC). In some embodiments, the individual has NO bladdercancer (e.g., MIBC). In some embodiments, the individual has N1, N2, orN3 bladder cancer (e.g., MIBC). In some embodiments, the individual hascT2 bladder tumor or cT3 bladder tumor (e.g., MIBC). In someembodiments, the individual has Ta, Tis, T1, T2 (e.g., T2a and/or T2b),T3 (e.g., T3a and/or T3b), T4 (e.g., T4a and/or T4b) bladder cancer(e.g., MIBC). In some embodiments, the individual has NO and M0 bladdercancer (e.g., MIBC). In some embodiments, the individual has cT2, NO, M0MIBC. In some embodiments, the individual has cT3, NO, M0 MIBC.

In some embodiments, the individual is at least about 60, 65, 70, 75,80, 85 or 90 years old. In some embodiments, the individual has acompromised immune system.

In some embodiments, the individual is human.

II. Intravesicular (Intravesical) Devices Device Shape

In some embodiments, the methods provided herein comprise administeringgemcitabine using an intravesicular (intravesical) device. In someembodiments, the intravesicular (intravesical) device comprises adeployment shape and a retention shape. For example, the device may beelastically deformable between a relatively straightened or uncoiledshape suited for insertion through a lumen (e.g., the urethra) into thebladder of the individual (the deployment shape) and a retention shapesuited to retain the device within the bladder. For the purposes of thisdisclosure, terms such as “relatively expanded shape,” “relativelyhigher-profile shape,” or “retention shape” generally denote any shapesuited for retaining the device in the intended implantation location,including but not limited to a pretzel shape or other coiled shape(e.g., comprising bi-oval or overlapping coils) that is suited forretaining the device in the bladder. The retention shape provides thatthe device resists becoming entrained in urine and excreted when theindividual voids. Similarly, terms such as “relatively lower-profileshape” or “deployment shape” generally denote any shape suited fordeploying the drug delivery device into the body, for example thebladder, including, but not limited to, including a linear or elongatedshape that is suited for deploying the device through the workingchannel of catheter, cystoscope, or other deployment instrumentpositioned in the urethra. In embodiments, the drug delivery device maynaturally assume the relatively expanded shape and may be deformed,either manually or with the aid of an external apparatus, into therelatively lower-profile shape for insertion into the body. For example,the external apparatus may be an inserter configured for transurethralinsertion. Once deployed the intravesicular (intravesical) device mayspontaneously or naturally return to the initial, relatively expandedshape for retention in the body. In some embodiments, the device behaveslike a spring, deforming in response to a compressive load (e.g.,deforming the device into a deployment shape) but spontaneouslyreturning to a retention shape once the load is removed.

In some embodiments, the shape changing functionality of theintravesicular (intravesical) device described in the precedingparagraph may be provided by including a shape retention frame (i.e., a“retention frame”) in the device, such as those disclosed in the patentapplications publications identified above and incorporated herein byreference. In some embodiments, the device may include a retention framelumen in which the retention frame, which may be an elastic wire, e.g.,a superelastic alloy such as nitinol, is secured. The retention framemay be configured to return spontaneously to a retention shape, such asa “pretzel” shape or another coiled shape, such as those disclosed inthe applications previously incorporated. In particular, the retentionframe may retain the device in the body, such as in the bladder. Theretention shape provides that the device resists becoming entrained inurine and excreted when the individual voids. For example, the retentionframe may have an elastic limit and modulus that allows the device to beintroduced into the body in a relatively lower-profile shape, permitsthe device to return to the relatively expanded shape once inside thebody, and impedes the device from assuming the relatively lower-profileshape within the body in response to expected forces, such as thehydrodynamic forces associated with contraction of the detrusor muscleand urination. Thus, the device may be retained in the individual'sbladder once deployed, limiting or prevent accidental expulsion.

In some other embodiments, the shape changing functionality of theintravesicular (intravesical) device may be provided by forming thedevice housing at least in part of a thermally shape set elasticpolymer.

The material used to form the device body (i.e., the housing), at leastin part, may be elastic or flexible to permit moving the device betweendeployment and retention shapes. When the device is in the retentionshape, the retention frame portion may tend to lie inside the drugreservoir portion as shown, although the retention frame portion can bepositioned inside, outside, above, or below the drug reservoir portionin other cases. The material used to form the device body may be waterpermeable so that solubilizing fluid (e.g., urine) can enter the drugreservoir portion to solubilize the non-liquid forms of the gemcitabine,immunomodulating agent, additional therapeutic agent, functional agent,or combination thereof contained in the drug reservoir once the deviceis deployed into the bladder. For example, silicone or anotherbiocompatible elastomeric material may be used. In other embodiments,the device body may be formed, at least in part, of a water-impermeablematerial.

In some embodiments, the device body is made of an elastic,biocompatible polymeric material. The material may be non-resorbable orresorbable. Example non-resorbable materials include synthetic polymersselected from poly(ethers), poly(acrylates), poly(methacrylates),poly(vinyl pyrolidones), poly(vinyl acetates), poly(urethanes),celluloses, cellulose acetates, poly(siloxanes), poly(ethylene),poly(tetrafluoroethylene) and other fluorinated polymers, andpoly(siloxanes). Example resorbable materials, specificallybiodegradable or bioerodible polymers, include synthetic polymersselected from poly(amides), poly(esters), poly(ester amides),poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudo poly(aminoacids), poly(glycerol-sebacate), poly(lactic acids), poly(glycolicacids), poly(lactic-co-glycolic acids), poly(caprolactones),poly(caprolactone) (PC) derivatives, amino alcohol-based poly(esteramides) (PEA) and poly (octane-diol citrate) (POC), and other curablebioresorbable elastomers. PC-based polymers may require additionalcross-linking agents such as lysine diisocyanate or2,2-bis(e-caprolacton-4-yl)propane to obtain elastomeric properties.Copolymers, mixtures, and combinations of the above materials also maybe employed.

In some embodiments, the device body comprises silicone, thermoplasticpolyurethane, ethyl vinyl acetate (EVA), or a combination thereof. Insome embodiments, the device body comprises two different thermoplasticmaterials, one of which is a hydrophilic thermoplastic polyurethane andis drug permeable, with the other being drug-impermeable. The drugimpermeable material may be a selected from the group consisting ofhydrophilic polyurethane, hydrophilic polyesters, and hydrophilicpolyamides. The device body may comprise an annular tube formed by anextrusion or coextrusion process, using one or more these materials, asdescribed in U.S. Publication 2016/0310715.

Drug Core

In embodiments in which the anti-metabolite is delivered from anintravesical (intravesicular) drug delivery device, the drug may behoused in the device in various forms, which may depend on theparticular mechanism by which the device controllably releases the druginto fluid (e.g., urine) in the bladder. In some embodiments, the drugis provided in a solid, semi-solid, or other non-liquid form, whichadvantageously may facilitate stable storage of the drug before thedevice is used and advantageously may enable the drug payload of thedevice to be stored in smaller volume than would be possible if the drugwere housed in the form of a liquid solution. In an embodiment, thenon-liquid form is selected from tablets, granules, powders, semisolids(e.g., an ointment, cream, paste, or gel), capsules, and combinationsthereof. In one embodiment, the drug is in the form of a plurality oftablets, such as mini-tablets described in U.S. Pat. No. 8,343,516.

For example, the anti-metabolite, may take such forms as suspensions,solutions, or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Alternatively, the active ingredients may be in powder form,obtained by aseptic isolation of sterile solid or by lyophilization fromsolution, for constitution with a suitable vehicle, e.g., sterile,pyrogen-free water, before use.

In one embodiment, the gemcitabine is formulated with one or moreexcipients that include a viscosity enhancing agent to control releaseof solubilized gemcitabine from a release aperture in the devicehousing. In another embodiment, the device reservoir includes bothgemcitabine and a viscosity enhancing agent, but they are notco-formulated and instead are provide in discrete regions within thereservoir, e.g., as separate tablets. Suitable viscosity enhancingagents, including but not limited to polyethylene oxide (PEO), are knownin the pharmaceutical arts. In some variations of the embodiment, theviscosity enhancing agent may be provided, e.g., formulated, with ureaor another osmotic agent.

In one embodiment, the gemcitabine is administered to the individualwith a solubility enhancing agent. In an embodiment, the solubilityenhancing agent is urea. In one embodiment, the urea is provided in atablet or other solid form and loaded with the gemcitabine in the drugreservoir of an intravesicular (intravesical) drug delivery device. Theurea may also function, depending on the device, as an osmotic agent tofacilitate generation of an osmotic pressure in a drug reservoir. In aparticular embodiment, the gemcitabine and the osmotic agent areconfigured as separate tablets (or other solid forms) positioned withindifferent regions of the drug reservoir as described in PCT WO2015/026813 (Lee et al.) which is incorporated by reference herein.

In some embodiments the device may comprise a drug reservoir lumen. Insome of these embodiments, each drug reservoir lumen may hold one orseveral drug tablets or other solid drug units. In one embodiment, thedevice holds from about 10 to 100 cylindrical drug tablets, such asmini-tablets, among a number of discrete drug reservoir lumens. Incertain embodiments, the mini-tablets may each have a diameter of about1.0 to about 3.3 mm, such as about 1.5 to about 3.1 mm, and a length ofabout 1.5 to about 4.7 mm, such as about 2.0 to about 4.5 mm.

Drug Housing

The release of gemcitabine from the intravesicular (intravesical)devices described herein may be driven and controlled by differentmechanisms of action. In various embodiments, the drug may be releasedfrom the intravesicular (intravesical) drug delivery device by diffusionthrough a wall of the drug housing, by diffusion through one or moredefined apertures in a wall of the drug housing, by osmotic pressurethrough an aperture in the drug housing, by osmotic pressure through oneor more transiently formed microchannels, by erosion of a drugformulation in contact with urine in the bladder, or by a combinationthereof. In some embodiments, drug release is controlled by drugdiffusion through a drug-permeable polymer or matrix component definingpart of the device housing. In one embodiment, the device includes adrug-permeable polymer component.

The size of the housing, including the thickness of the wall, may beselected based on the volume of drug (and functional agent, if any)formulation(s) to be contained, the desired rate of delivery of the drugfrom the device body/housing, the intended site of implantation of thedevice within the body, the desired mechanical integrity for the device,the desired release rate or permeability to water and urine, the desiredinduction time before onset of initial release, and the desired methodor route of insertion into the body, among others. In embodiments inwhich the housing is a tube, the tube wall thickness may be determinedbased on the mechanical properties and water permeability of the tubematerial, as a tube wall that is too thin may not have sufficientmechanical integrity while a tube wall that is too thick may experiencean undesirably long induction time for initial drug release from thedevice and/or may not have sufficient flexibility to permit deliverythrough a urethra or other narrow body lumen.

In some embodiments, the housing may be an elongated, annular tubehaving an inner diameter from about 2 mm to about 5 mm. The drug, andfunctional agent if any, may be solid tablets having a diametersubstantially the same as the inner diameter of the elongated annulartube. In some embodiments, the housing holds one or more first drugunits comprising a drug and one or more second drug units comprising afunctional agent which facilitates release of the drug. One or more ofthe first unit tablets may fill a length from about 1 cm to about 3 cmof the lumen of the tube, and one or more of the second unit tablets mayfill a length from about 10 cm to about 15 cm of the lumen of the tube.In one embodiment, the ratio of volume of the first unit(s) to volume ofthe second unit(s) is from about 0.05 to about 0.5. Other lengths andratios of the tablet payloads are envisioned.

In some embodiments, the housing may be an elongated, annular tubehaving a wall thickness from 0.1 to 0.4 mm, such as a wall thickness of0.2 mm. The housing material may comprise one or more biocompatibleelastomers. The housing material may be selected such that the housinghas a durometer from 25 A to 80 A, such as 25 A, 50 A, 65 A, 70 A, or 80A.

In various embodiments, the intravesicular (intravesical) device mayrelease the drug continuously or intermittently to achieve aconcentration of the drug in the bladder that produces a sustained,therapeutically effective concentration of the drug in urine in thebladder as described in the methods provided herein. For example, over aperiod from 1 hour to 1 month, for example from 2 hours to 2 weeks, from6 hours to 1 week, from 24 hours to 72 hours, etc. In certainembodiments, the intravesicular (intravesical) device may release thegemcitabine in an amount of from 1 mg/day to 1000 mg/day, for examplefrom 20 mg/day to 300 mg/day or from 25 mg/day to 300 mg/day. In certainembodiments, these release rates are provided over a treatment period asdescribed herein. In certain embodiments, these release rates areprovided over a treatment period from 14 days to 21 days.

Osmotic and Diffusion Systems

Following in vivo deployment, the device releases the drug. Release mayoccur, as described above, due to an osmotic pressure gradient betweenthe interior and exterior of the device, the drug passing through one ormore orifices or passing pores in the device under the force of osmoticpressure. Release may also occur by diffusion, whereby the drug passesthrough one or more orifices or passing pores in the device and/orthrough a drug-permeable wall of the device, due to a drug concentrationgradient between the interior and exterior of the device. Combinationsof these release modes within a single device are possible, and in someembodiments are preferred in order to achieve an overall drug releaseprofile not readily achievable from either mode individual.

In some embodiments in which the device comprises a drug in a solidform, elution of drug from the device occurs following dissolution ofthe drug within the device. Bodily fluid enters the device, contacts thedrug and solubilizes the drug, and thereafter the dissolved drugdiffuses from the device or flows from the device under osmotic pressureor via diffusion. For example, the drug may be solubilized upon contactwith urine in cases in which the device is deployed in the bladder. Incertain embodiments, a water permeable wall portion of the housing ispermeable to the drug in aqueous solution, such that solubilized drug isreleased via the wall portion, also referred to herein as “trans-walldiffusion.” After the device is implanted, water or urine permeatesthrough the wall, enters the reservoir, and solubilizes the functionalagent and/or drug. The drug then diffuses directly through the wall at acontrolled rate, due to a drug concentration gradient between theinterior and the exterior of the device. For example, the housing and/orany water or drug permeable wall portions may be silicone, athermoplastic polyurethane, ethylene-co-vinyl acetate (EVA), or acombination thereof.

In some embodiments, the intravesicular (intravesical) device maycontain a unit concentration of about 225 mg of gemcitabine. In some ofthese embodiments, the device may be configured to deliver about 100 toabout 225 mg of gemcitabine (e.g., about 140 mg, about 160 mg, about 180mg, about 200 mg, or about 220 mg) mg of gemcitabine to the individualover a 3 week period.

In a particular embodiment, the drug delivery device may include apermeation system as described in WO2014/145638 and U.S. Publication2016/0310715, which are herein both incorporated by reference in itsentirety. In some embodiments, the drug delivery device includes ahousing having a closed drug reservoir lumen bounded by a first wallstructure and a hydrophilic second wall structure; and a drugformulation comprising gemcitabine contained in the drug reservoirlumen, wherein the first wall structure is permeable or impermeable towater and impermeable to the drug, and the second wall structure ispermeable to the gemcitabine.

In some embodiments, the device housing has walls bounding and definingthe drug reservoir of the device that are made of a first material thatserves as the first wall structure and a second material that serves asthe second wall structure, such that drug release occurs essentiallyonly through the second material. In one embodiment, the device does notinclude an aperture; drug release is only by diffusion through thesecond wall structure. As used herein, the terms “impermeable to thedrug” and “impermeable to water” refer to the wall structure beingsubstantially impermeable to the drug or to water, such that essentiallyno drug or water is released via the wall structure over the therapeuticrelease period. For use in the bladder, it is desirable that the devicebe compliant (i.e., easily flexed, soft feeling) during detrusor musclecontraction in order to avoid or mitigate discomfort and irritation tothe patient. Thus, the durometer of the first and second materials ofconstruction are a design consideration, and the proportion of a highdurometer material may be limited in constructing a device housing of agiven size while keeping it suitably compliant in the bladder. Forexample, Tecophilic™ thermoplastic polyurethane (Lubrizol Corp.) mayhave a Shore hardness greater than 70 A, such as from 80 A to 65 D,while silicone tubing which may have a Shore hardness of from 50 A to 70A. Accordingly, it can be advantageous to utilize the combination ofthese two different polymeric materials, rather than making the deviceentirely of the water-swelling hydrophilic, drug-permeable secondmaterial.

The arrangement of the first and second wall structures can take avariety of forms. In certain embodiments, the first wall structure is acylindrical tube and the second wall structure is an end wall disposedat least one end of the cylindrical tube, or the first wall structureand the second wall structure are adjacent one another and together forma cylindrical tube. That is, drug release is controlled by drugdiffusion through a drug-permeable component defining a portion of theclosed device housing. The drug-permeable wall structure may be located,dimensioned, and have material properties to provide the desired rate ofcontrolled drug diffusion from the device. In one embodiment, the drugpermeable wall may include a disk stabilized in the lumen of a tube ator near an end of the tube, optionally sandwiched between an innerwasher and an outer washer. In another embodiment, the drug permeablewall is part of a sidewall of a tubular housing, or part of an end pluglocated at the end of a tubular housing.

The length and width, e.g., wall portion formed of the water permeablematerial are selected to provide a desired rate of water flux into thereservoir defined by device housing. In one embodiment, the width of thewater permeable wall portion may be quantified by the arc angle definingthe wall when viewed in cross-section normal to the luminal axis. Thewater permeable region(s) of the device housing can be controlled togive a selected area of, and thus rate for, osmotic water imbibition,and yet advantageously maintain suitable overall dimensions andelasticity of the device, formed of suitable biocompatible elastomers.Advantageously by forming the device housing by a co-extrusion process,the structural variations of the water permeable region(s) can becreated with conventional co-extrusion equipment by selection of theprocessing parameters, thereby beneficially providing the ability tocost-effectively manufacture multiple structural device configurations.In some embodiments, the length of the water permeable regions(s) runsalong only a portion of the overall length of the device. In such anembodiment, larger arc angles of the water permeable region(s) cantherefore be employed while keeping the rate of drug release at adesirable level over an extend period of time.

In some embodiments, the wall may have a varied thickness over thecircumference of the wall, for example the drug permeable portion mayhave a thickness that is less than the thickness of the drug impermeableportion. Moreover, the thinner drug permeable wall structure may bedisposed at various positions relative the adjacent, thicker drugimpermeable wall structure. In some embodiments, drug release iscontrolled by drug diffusion through a drug-permeable component defininga portion of the closed device housing. The drug-permeable wallstructure may be located, dimensioned, and have material properties toprovide the desired rate of controlled drug diffusion from the device.

In some embodiments, the drug delivery device comprises a housingcomprising a first wall structure and a second wall structure that areadjacent one another and together form a tube defining a drug reservoirlumen; and a drug contained in the drug reservoir lumen, wherein: (i)the second wall structure, or both the first wall structure and thesecond wall structure, are permeable to water, (ii) the first wallstructure is impermeable to the drug and the second wall structure ispermeable to the drug, such that the drug is releasable in vivo bydiffusion through the second wall structure, (iii) the second wallstructure comprises less than 90 percent of a cross sectional area ofthe tube, in a cross section normal to the longitudinal axis of thetube, (iv) and the first wall structure comprises a first polyurethanecomposition.

In some embodiments, the device comprises an elongated, elastic housinghaving a drug reservoir lumen extending between a first closed end and asecond closed end; and a drug contained in the drug reservoir lumen,wherein (i) the housing comprises a tubular wall structure whichcomprises: a first annular segment formed entirely of a first materialwhich is impermeable to the drug, and a second annular segment formed atleast partially of a second material which is permeable to the drug andconfigured to release the drug in vivo by diffusion through the secondmaterial in the second annular segment, and (ii) the first annularsegment has a first end which is integrally formed and connected with afirst end of the second annular segment.

In some embodiments, the walls that define the drug reservoir lumens mayhave varying thickness. Housings with walls of different thicknesses mayimprove the housing's flexibility, compressibility, or both. Differentwall thicknesses also may aid in securing a solid drug unit in the drugreservoir lumens.

In some embodiments, the intravesicular (intravesical) device body, orhousing, may include openings (e.g., at the opposed ends of an annulartube) in need of sealing following loading of the drug reservoir withthe drug payload, during the assembly process. Any of these definedopenings or ends of the housings, including the monolithic housing andmodular housing units, may be sealed, if desired to close off anopening. This sealing may be accomplished with a sealing substance orstructure. The sealing structure may be formed of biocompatiblematerial, including a metal such as stainless steel, a polymer such assilicone, a ceramic, or sapphire, or adhesive, among others orcombinations thereof. The sealing substance or structure may bebiodegradable or bioerodible. In one embodiment, a medical gradesilicone adhesive or other adhesive is loaded into the opening in afluid or workable form and then cure within the housing opening to sealit. In some embodiments, the housing includes one or more predefinedapertures for release of the drug from the device. These drug-releaseapertures are not the defined openings which are sealed. In otherembodiments, the housing does not include a predefined drug-releaseaperture.

In some embodiments the device releases drug without a predefined drugrelease aperture (i.e., orifice). Release of drug from a device withouta predefined drug-release aperture may be driven by diffusion or osmoticpressure. Examples of such suitable “no-orifice” release systems aredescribed in PCT Patent Application Publication No. WO 2014/144066 (TB130) and U.S. Patent Application Publication No. 2014/0276636 (TB 134),which are incorporated herein by reference.

In a particular embodiment, the drug delivery device may include anosmotic system as described in U.S. Publication 2016/0199544, U.S. Pat.No. 8,679,094, and U.S. Publication 2016/0008271, which are hereinincorporated by reference.

In some embodiments, the device comprises a housing defining areservoir; a first unit contained within the reservoir, the first unitcomprising a drug; and a second unit contained within the reservoir in aposition distinct from the first unit, wherein the second unit comprisesa functional agent that facilitates in vivo release of the drug fromhousing. In some embodiments, the first unit comprises one or more solidtablets which comprise at least one drug (such as gemcitabine), and thesecond unit comprises one or more solid tablets (e.g., which comprise anosmotic agent, such as urea). In some embodiments, the housing is in theform of an elongated elastomeric tube having a lumen (i.e., thereservoir) in which all of the solid tablets of the first and secondunits are aligned and contained. The diameter of the solid tablets maybe substantially the same as the diameter of the lumen.

When osmotic release is the desired drug release mode, the functionalagent in the second units may include an osmotic agent that facilitatesosmotic release of the drug. For example, the osmotic agent may have ahigher solubility than the drug, such that the osmotic agent expeditessolubilization and/or subsequent release of the drug. This beneficiallyallows for the delivery of low solubility or other drugs typically onlydelivered via diffusion, from osmotic delivery-based devices. The devicemay exhibit an induction period while a sufficient volume of functionalagent and/or drug are solubilized to achieve the osmotic pressuregradient.

Subsequently, the device may exhibit a zero-order release rate for anextended period, followed by a reduced, non-zero-order release rate overa decay period. A desired delivery rate can be achieved bycontrolling/selecting various parameters of the device, including butnot limited to the surface area and thickness of the water permeablewall; the permeability to water of the material used to form the wall;the shape, size, number and placement of the apertures; and thedissolution profiles of the drug and functional agent.

The devices described herein may also be configured to release drug viadiffusion, alone or in combination with osmotic release. The device maybe configured to allow the solubilized drug to pass through a portion ofthe housing or one or more apertures therein.

Alternatively, or in combination with a water permeable wall portion,the housing may include at least one aperture configured to permit afluid to enter the reservoir in vivo. The housing may also include oneor more apertures or passing pores configured to permit solubilized drugto pass there through.

In some embodiments of the osmotic system, the device housing includes afirst elastomeric material that is water permeable and a secondelastomeric material that is water impermeable, wherein both materialsare selected to be impermeable to the drug contained in the housing.

Erosion-Based Systems

In some embodiments, which may be used with tablets comprisinglow-solubility drugs, the drug is provided in tablet form secured in thedevice with exposed tablet faces, such that release of drug from thedevice occurs by controlled erosion/dissolution, as described in U.S.Pat. No. 9,107,816. In some embodiments, the device may comprise modularhousings. The modular housings are typically formed from at least twoseparate housing units, each unit housing at least one solid drug unit.The material from which each housing unit is formed defines at least onedrug reservoir lumen capable of housing a solid drug unit. The drugreservoir lumens may have one or more defined openings. For example, thedrug reservoir lumen may have two opposed openings which exposecorrespondingly opposed end surfaces of the at least one solid drug unithoused therein. In certain embodiments, the at least two separatehousing units in the modular housings are connected, directly orindirectly, by a retention frame. In some embodiments, the modularhousing units may be placed on the retention frame to form a “bracelet”design. The devices may have one housing unit or a plurality of housingunits. The number of housing units may be limited only by the size ofthe retention frame by which they are connected.

In some embodiments, one or more of the separate housing units includesa retention frame lumen through which a shared retention frame isextended. In certain embodiments, the retention frame lumen and the drugreservoir lumen of each housing unit are arranged parallel to eachother. In particular embodiments, the retention frame lumen and the drugreservoir lumen of each housing unit are arranged perpendicular to eachother. In further embodiments, the retention frame lumen and the drugreservoir lumen of each housing unit are arranged at an angle other than0° (parallel) and 90° (perpendicular), such as 5, 10, 30, 45, 60, or85°. In further embodiments, the devices described herein include two ormore housing units with at least two of the following configurations:(1) the retention frame lumen and drug reservoir lumen are arrangedsubstantially parallel to each other, (2) the retention frame lumen anddrug reservoir lumen are arranged substantially perpendicular to eachother, and (3) the retention frame lumen and drug reservoir lumen arearranged at an angle other than 0° (parallel) and 90° (perpendicular).

Integrated Silicone-Drug Delivery Systems

In some embodiments, the device may comprise an elastic polymer-drugmatrix as described in WO2015/200752, which is herein incorporated byreference in its entirety.

Devices with Multiple Release Portions

In particular embodiments, the device includes at least two drug releaseportions, at least one release portion releasing drug at a differentrate than another release portion as described in WO2011/031855 which isherein incorporated by reference in its entirety. The release portionsmay achieve different release rates by having different configurations,by housing different drug formulations, or by employing differentrelease mechanisms, among others or combinations thereof. The releaseportions may be combined to achieve a desired release profile. Forexample, the device may include release portions that exhibit differentinduction or lag times before the onset of initial release, that releasedrug at different rates or according to different release curves afterthe onset of release, or that release drug for different periods beforethe drug load is substantially exhausted, among others or combinationsthereof. The disparate release portions may be combined to achieve adesired release profile from the drug delivery device as a whole, suchas a release profile that demonstrates a relatively short initial lagtime and thereafter demonstrates continued release at a relativelyconstant rate over an extended period.

In some embodiments, the devices are loaded with drugs in the form of anumber of solid drug tablets, which may be smaller in size thanconventional drug tablets. Because the devices control release of thedrug into the body, the drug itself may include little or no excipientsthat control drug release. Instead, the excipients present in the drugtablets may be present primarily or completely to facilitate thetableting process or solubilization in vivo. Thus, the devices mayprovide a high drug payload on a volume or weight basis, yet the devicesmay be small enough for in vivo deployment in a minimally invasivemanner.

The drug housing also permits the egress of drug, in either liquid orsemi-solid form as implanted or following in vivo solubilization. Thewall may be formed from a drug-permeable material that permits drugefflux through the drug housing along its entire length. The wall alsomay be formed from a material that is semi-permeable to the drugdepending at least in part on the drug form. For example, the wall maybe permeable to the drug in one form, such as a charged form, but notanother form, such as uncharged form (e.g., base form versus salt form).The wall also may include one or more openings or passageways formedcompletely through it that permit drug to exit the drug housing.

The drug housing houses a drug in the form of a number of solid drugtablets, which are aligned within the drug housing in a serialarrangement and are enclosed within the drug housing with sealingstructures, such as plugs, that close entry openings on opposite ends ofthe drug housing. Interstices or breaks formed between adjacent drugtablets permit the drug tablets to move with reference to each other sothat the device is flexible despite being loaded with drug in solidform.

The drug portion can have any combination of the characteristics orconfigurations described herein, meaning the aperture may be provided,omitted, substituted with a passing pore, or augmented with additionalapertures or passing pores; the housing may have a porous wall with anopen-cell structure or a closed-cell structure; one or more degradabletiming structures or release modulating structures may be associatedwith the housing, or any combination thereof.

The drug tablets may be aligned in any arrangement other than a serialarrangement, depending on the configuration of the drug housing. Thedrug tablets may fill any portion of the drug housing other than theentire drug housing as illustrated. A filling material such as siliconeadhesive can be used to fill any portion of the drug housing that is notloaded with drug tablets, or air may be used, increasing the buoyancy ofthe device. The composition of the drug tablets may be the same or mayvary along the device. The drug also may be in forms other than a drugtablet, such as other liquid, semi-solid, or solid forms (e.g.,granules).

In particular embodiments, the drug delivery device includes at leasttwo discrete or segregated drug portions associated with a singleretention portion. The drug portions may be separate drug housings eachassociated with the retention portion, or the drug portions may beseparate areas within a single drug housing that is associated with theretention portion.

Each drug portion may be defined by a portion of the wall of the drughousing and at least one partition structure, which separates the drugportion from a second drug portion. The partition structure may be aplug inserted into the housing, such as a cylinder, sphere, or disk,among others, which is secured in place due to its size or with anadhesive. The partition structure also may be a portion of the housingformed directly therein, such as by molding.

A device with at least two discrete portions may be suited forcontrolled release of at least two drug payloads from a correspondingnumber of drug reservoirs. The two discrete portions may have the sameconfigurations or different configurations as described herein. The twodrug payloads may be the same as each other or may differ from eachother with reference to content, such as active ingredient content orexcipient content; form, such as salt form or base form; state, such asliquid, semi-solid, or solid state; among others or combinationsthereof. Thus, the two discrete portions may release the two drugpayloads at the same time or at different times, at the same rate or atdifferent rates, via the same release mechanisms or different releasemechanisms, or any combination thereof.

For example, one drug portion may be configured to release its drugpayload relatively quickly after implantation and another drug portionmay be configured to experience an induction time before beginningrelease, or a combination thereof. The onset of release of two payloadsin different drug portions can be staged. Examples of quick release drugportions include a drug portion that operates as a relativelyfast-acting osmotic pump, such as a silicone tube having a relativelythinner wall, a drug portion that is loaded with drug in a quick releaseform, such as liquid form or a specially formulated solid form, a drugportion associated with a relatively fast-acting degradable timingstructure, or combinations thereof. Thus, the device may release drugduring an initial, acute phase and during a maintenance phase.

As another example, one drug portion may be configured to release itsdrug payload at a relatively faster rate than the other drug payload.For example, one drug portion may house a drug payload with low watersolubility for diffusive release that is initiated relatively soon afterimplantation, and another drug portion may house a drug payload that ishighly water soluble for osmotic release after an induction period. Asanother example, one drug portion may house a drug payload in a liquidstate for quick release through an aperture having a fast-actingdegradable timing membrane, and another drug portion may house anotherdrug payload of solid tablets for slow release following solubilizationin vivo. As still another example, one drug portion may have arelatively solid wall while another drug portion may have a number ofapertures or pores formed through its wall, which may increase therelease rate due to diffusion, or a closed-cell porous wall, which mayincrease the release rate due to increased permeation of water or drugthrough the wall.

The release portions may be combined to achieve a desired releaseprofile. For example, the device may include release portions thatexhibit different induction or lag times before the onset of initialrelease, that release drug at different rates or according to differentrelease curves after the onset of release, or that release drug fordifferent periods before the drug load is substantially exhausted, amongothers or combinations thereof. The disparate release portions may becombined to achieve a desired release profile from the drug deliverydevice as a whole, such as a release profile that demonstrates arelatively short initial lag time and thereafter demonstrates continuedrelease at a relatively constant rate over an extended period.

By combining multiple distinct drug portions in a single device, thedevice may exhibit a desired release profile of an anti-metabolite. Therelease profile from the device as a whole may be the sum of the releaseprofiles of the discrete portions, for example, with the first portionexhibiting minimal lag time before the onset of release, the secondportion exhibiting a short induction period as the osmotic pressuregradient develops, and the third portion exhibiting a longer delaybefore onset as the degradable structure dissolves or degrades. Oncerelease begins from any one portion, the release rate may be relativelyzero-order for an extended period, followed by a period of decay. Itshould be noted that the three discrete portions are examples, and thatany number or combination of discrete portions may be used to achievethe desired release profile.

Because the different drug portions are merely segregated areas withinin a single tubular housing, the device advantageously may be relativelysimple to construct and deploy, and yet the different drug portionsexhibit different release profiles due to the different drug payloads,aperture placement, and degradable timing structures. In otherembodiments in which the drug portions use, for example, walls ofdifferent materials, thicknesses, or porous cell structures, the housingmay vary along its length or separate drug housings may be used. Thus,controlled release may be achieved in a range of manners.

Gels

In another embodiment, a coating substance may be intravesically appliedto the bladder wall (e.g., to an area of the urothelium inside theurinary bladder), wherein the coating substance includes the gemcitabineor other drug and one or more excipient materials that promote adherenceof the coating substance to the bladder wall and provides continuouscontrolled release of the drug over the treatment period. The coatingsubstance may be a mucoadhesive formulation, such as gels, ointments,creams, pastes, films, emulsion gels, tablets, polymers, or acombination thereof. Mucoadhesive formulation polymers may includehydrogels or hydrophilic polymers, polycarbophil (i.e. Carbopols, etc.),chitosan, polyvinylpyrrolidone (PVP), lectin, polyethyleneglycolatedpolymers, celluloses, or a combination thereof. Suitable cellulosesinclude methyl cellulose (MC), carboxymethyl cellulose (CMC),hydroxypropyl cellulose (HPC), or combinations thereof. The coatingsubstance may include a permeation enhancer. Non-limiting examples ofpermeation enhancers include dimethyl sulfoxide (DMSO), sodiumcarboxymethyl cellulose (NaCMC), lipids, surfactants, or combinationsthereof. A coating substance may be deployed in the bladder so that thecoating substance engages the bladder wall.

The coating substance may be deployed in the bladder using a deploymentinstrument. The deployment instrument may be any device designed tonavigate natural lumens of the body to reach the intended implantationsite. For deployment in the bladder, the deployment instrument is sizedand shaped for passing through a urethra of a patient to a bladder. Thedeployment instrument may be a known device, such as a catheter orcystoscope, or a specially designed device. The deployment instrument isused to deploy the coating substance into the body and is subsequentlyremoved from the body, leaving the coating substance wholly implanted inthe body. Once so implanted, the coating substance may release drug intothe body for an extended period. A comparable procedure can be used todeploy any of the devices or drugs described herein into other parts ofthe body through other natural lumens. For example, a deploymentinstrument can be used to deploy a liquid drug or drug formulation intothe bladder by passing the deployment instrument through a urethra.

III. Exemplary Embodiments

Embodiment 1. A method of providing maintenance therapy for anindividual, wherein the maintenance therapy follows at least oneprevious therapy, wherein the maintenance therapy comprisesadministering gemcitabine continuously to the individual two or moretimes during two or more delivery periods, wherein the gemcitabine isdelivered locally to the bladder of the individual, wherein eachdelivery period is at least one week, wherein there is a rest periodbetween each delivery period of at least one month, and wherein theindividual has a urothelial carcinoma of the lower tract.

Embodiment 2. A method of maintenance therapy following at least oneprevious therapy for an individual having a urothelial carcinoma of thelower tract, comprising administering gemcitabine continuously andlocally to the bladder of the individual two or more times during two ormore delivery periods, wherein each delivery period is at least one weekand there is a rest period between each delivery period of at least onemonth.

Embodiment 3. The embodiment of embodiment 1 or 2, wherein thegemcitabine is delivered into the bladder by an intravesicular device.

Embodiment 4. The method of embodiment 3, wherein the intravesiculardevice contains 225 mg gemcitabine.

Embodiment 5. The method of any of embodiments 1-4, wherein the deliveryperiods are each 3 weeks.

Embodiment 6. The method of any of embodiments 1-5, wherein the restperiod is about 3 months.

Embodiment 7. The method of any of embodiments 1-6, wherein thegemcitabine is delivered at a dose from about 1 mg/day to about 300mg/day during delivery periods.

Embodiment 8. The method any one of claims 1-7, wherein theconcentration of gemcitabine in the urine is from about 1 μg/mL to about10 μg/mL during the first and second delivery period.

Embodiment 9. The method of embodiment 8, wherein the concentration ofgemcitabine in the urine is about 10 μg/mL during the delivery periods.

Embodiment 10. The method of any one of embodiments 1-9, wherein theindividual is ineligible for or has refused cisplatin-basedchemotherapy.

Embodiment 11. The method of any one of embodiments 1-10, wherein theindividual is unfit for, ineligible for, or has refused a radicalcystectomy.

Embodiment 12. The method of any one of embodiments 1-11, wherein theindividual has muscle invasive bladder cancer.

Embodiment 13. The method of any one of embodiments 1-11, wherein theindividual has non-muscle invasive bladder cancer.

Embodiment 14. The method of any one of embodiments 1-13, wherein therest period between the delivery periods is about 3 months.

Embodiment 15. The method of any one of embodiments 1-14 comprising 4delivery periods, wherein the rest period between each delivery periodis about 3 months.

Embodiment 16. The method of any one of embodiments 1-14, wherein therest period between each delivery period is about 3 months, and whereinthe gemcitabine is delivered every 3 months for the lifetime of theindividual.

Embodiment 17. A method of treating a urothelial carcinoma of the lowertract in an individual comprising a) administering to the individualcontinuously an effective amount of gemcitabine during an inductionphase; and b) administering to the individual continuously an effectiveamount of gemcitabine during a maintenance phase, wherein thegemcitabine is delivered locally to the bladder of the individual,wherein the induction phase and maintenance phases are separated by arest period, and wherein the induction phase is about 12 weeks.

Embodiment 18. A method of treating a urothelial carcinoma of the lowertract in an individual comprising a) administering to the individual aneffective amount of gemcitabine continuously and locally to the bladderof the individual during an induction phase of about 12 weeks; and b)administering to the individual an effective amount of gemcitabinecontinuously and locally to the bladder of the individual during amaintenance phase, wherein the induction phase and maintenance phasesare separated by a rest period.

Embodiment 19. A method of bladder preservation in an individualcomprising: a) administering to the individual continuously an effectiveamount of gemcitabine during an induction phase; and b) administering tothe individual continuously an effective amount of gemcitabine during amaintenance phase, wherein the gemcitabine is delivered locally to thebladder of the individual, wherein the induction phase and maintenancephases are separated by a rest period, wherein the induction phase isabout 12 weeks, and wherein the individual has a urothelial carcinoma ofthe lower tract.

Embodiment 20. A method of bladder preservation in an individual havinga urothelial carcinoma of the lower tract comprising: a) administeringto the individual an effective amount of gemcitabine continuously andlocally to the bladder of the individual during an induction phase ofabout 12 weeks; and b) administering to the individual an effectiveamount of gemcitabine continuously and locally to the bladder of theindividual during a maintenance phase, wherein the induction phase andmaintenance phases are separated by a rest period.

Embodiment 21. The method of any one of embodiments 17-20, wherein thegemcitabine is delivered by an intravesicular device.

Embodiment 22. The method of embodiments 21, wherein the intravesiculardevice contains 225 mg gemcitabine.

Embodiment 23. The method of any one of embodiments 17-22 wherein therest period between the induction phase and the maintenance phase isabout 3 months.

Embodiment 24. The method of any one of embodiments 17-23, wherein themaintenance phase comprises two or more gemcitabine delivery periods.

Embodiment 25. The method of embodiment 24, wherein the maintenancephase gemcitabine delivery periods are each separated by a rest periodof about 3 months.

Embodiment 26. The method of any of embodiments 17-25, wherein themaintenance phase gemcitabine delivery periods are each 3 weeks.

Embodiment 27. The method of any of embodiments 24-26, wherein thegemcitabine is delivered at a dose from about 1 mg/day to about 300mg/day during the induction phase or the maintenance phase deliveryperiods.

Embodiment 28. The method any one of embodiments 24-27, wherein theconcentration of gemcitabine in the urine is from about 1 μg/mL to about10 μg/mL during the induction phase or the maintenance phase deliveryperiods.

Embodiment 29. The method of any one of embodiments 17-28, wherein theindividual is ineligible for or has refused cisplatin-basedchemotherapy.

Embodiment 30. The method of any one of embodiments 17-29, wherein theindividual is unfit for, ineligible for or has refused a radicalcystectomy.

Embodiment 31. The method of any one of embodiments 17-30, wherein theindividual has muscle invasive bladder cancer.

Embodiment 32. The method of any one of embodiments 17-30, wherein theindividual has non-muscle invasive bladder cancer.

Embodiment 33. The method of any one of embodiments 1-32, wherein theindividual is human.

EXAMPLES Example 1

Subjects receive the first TAR-200 transuretherally via the TARISInserter on Study Day 0. On Study Day 21 (±3 days), this first TAR-200will be removed via flexible or rigid cystoscopy, and then the secondTAR-200 will be placed. TAR-200 is an intravesicular device thatcontains 225 mg of gemcitabine. This removal/replacement procedure isrepeated for a third and fourth dosing cycle in the induction period onStudy Days 42 (±3 days), and 63 (±3 days), respectively. The fourthTAR-200 will be removed on Study Day 84 (±3 days), and the 3-monthresponse assessment will be conducted. See FIG. 1

During the maintenance period, a 21-day dosing cycle occurs everyquarter (3 months) starting at approximately 6 months. Subjects maycontinue to undergo quarterly dosing cycles for 3 dosing cycles.

All subjects are assessed for clinical response every 3 months bycystoscopy, pelvic computed tomography (CT)/magnetic resonance imaging(MRI)/positron emission tomography (PET), and biopsy (at 12 weeks only,unless clinically indicated). Subjects are also assessed for symptomcontrol at 3, 6, 9, and 12 weeks, and approximately every month duringthe maintenance period.

The primary endpoint is assessment of safety and tolerability of 4consecutive 21 day TAR-200 dosing cycles.

The secondary endpoints are proportion of subjects with clinicalcomplete response (cCR), clinical partial response (cPR), stable disease(SD), and progression on the basis of visual lesions on cystoscopy,pelvic CT/MRI/PET, and biopsy. For purposes of this study, cCR means noevidence of the disease in the bladder or notes. cPR means in thepreviously NO subject, a down staging in bladder tumor burden to <pT2disease and no evidence of nodal disease burden or in the N1-N3 subject:a down staging in bladder tumor burden to <pT2 disease and no evidenceof an increase in the size of nodal disease burden or no evidence ofdown staging in bladder tumor burden and a decrease in the size of nodaldisease burden. Stable disease means persistent MIBC without evidence ofmetastasis. Progression means M1 disease or significant increase inburden of disease in bladder based upon cystoscopy and Ct/MRI/PET.Symptom control, defined as changes in bladder-related symptoms per theprotocol-specified bladder symptom and toxicity grading system. Othersecondary endpoints are time to intervention for symptom control,defined as the time from the date of the first TAR-200 insertion to thedate of intervention for symptom palliation; time to progression,defined as the time from the date of the first TAR-200 insertion to thedate of the first occurrence of progression; proportion of subjectsundergoing post-treatment interventions for the management of localsymptoms by 3, 6, 9, and 12 months; and proportion of subjects survivingat 12 months.

To be eligible to participate in this study, subjects must meet all ofthe following inclusion criteria at the time of enrollment:

1. Histological proof of muscle-invasive urothelial cell carcinoma ofthe bladder (T2-T4a). Subjects with mixed histology are required to havedominant transitional cell pattern. Subjects with evidence of nodaldisease below the aortic bifurcation may be included (cN0-cN3, M0).

2. Subject must have been as fully resected as possible per thephysician's judgment.

3. Subjects must be deemed unfit for RC due to comorbid conditions witha risk of mortality due to RC≥5% as estimated by the American College ofSurgeons risk calculator using the current procedure terminology code51595 or 51596 for cystectomy(http://riskcalculator.facs.org/RiskCalculator/PatientInfo.jsp).

4. Subjects must refuse cisplatin-based chemotherapy (and understand therisk and benefits of doing so) or be deemed ineligible forcisplatin-based chemotherapy by meeting at least one of the followingcriteria: World Health Organization (WHO) or Eastern CooperativeOncology Group (ECOG) performance status of ≥2 or Karnofsky performancestatus of 60-70%, Creatinine clearance (calculated or measured) ≤60mL/min, Common Terminology Criteria for Adverse Events (CTCAE) v4 Grade≥2, audiometric hearing loss, CTCAE v4 Grade ≥2 peripheral neuropathy,New York Heart Association ≥Class III heart failure.

5. Life expectancy of at least 4 months.

6. Adequate bone marrow, liver, and renal function, as assessed by thefollowing requirements conducted within 21 days prior to dosing:Hemoglobin ≥7.0 g/dL, Absolute neutrophil count (ANC) ≥1,500/mm3,Platelet count ≥75,000/mm3, Total bilirubin ≤2× the upper limit ofnormal (ULN), alanine aminotransferase (ALT) and aspartateaminotransferase (AST)≤3×ULN, Glomerular filtration rate ≥30% (≥30ml/min/1.73 m2)

7. Subjects must be willing to undergo a cystoscopy for InvestigationalProduct placement and removal.

Example 2

Twenty three patients were enrolled in the study as described inExample 1. The age range among the enrolled patients is from 50 to 98.The mean age is 82.6, and the median age is 84. The patients weretreated and assessed according to the methods described therein.Patients that accomplished a complete response, partial response orstable disease after the induction phase received the maintenance phasetreatment.

Results

Seven patients discontinued the study at some point during the inductiondue to various reasons. Out of the remaining sixteen patients, tenpatients have completed the full four cycles of treatment duringinduction period. Five patients have completed the assessment at Day180. The age range among the sixteen patients is from 50 to 98. The meanage is 81.75 and the median age is 84.

According to the evaluation at the end of the induction period (Day 84of the study), a 50% complete response rate and a 80% objective responserate (ORR) was achieved on a per protocol basis. See Table 1. On anIntent-to-Treat (ITT) basis (including all the 23 enrolled patients), a30% complete response rate and a 47% objective response rate wasachieved. Four consecutive doses were well tolerated in all tenpatients, and the evidence suggests a control of the symptoms and adurable effect at Day 180. Eight patients proceeded to the maintenancedosing.

TABLE 1 Whole- Histopathology Body Response Patient Tumor Stage (Biopsy)at Imaging Assessment Day 180 # Age at Diagnosis D 84 at D 84 at D 84Assessment 1 96 cT2 Negative NED CR NED 2 84 cT2 Negative NED CR N/A 383 cT2 Negative NED CR NED 4 72 cT2 Negative NED CR N/A 5 77 cT2Negative NED CR N/A 6 88 cT2 Tis NED PR N/A 7 50 cT2 T1 NED PR N/A 8 85cT2 w/ Negative Stable PR Nodal Hydronephrosis Left Progression IliacNode 9 80 cT2 w/ Residual NED SD NED Hydronephrosis MIBC 10 98 cT3Residual NED SD Progression/ w/ Trigonal MIBC Death at 6 Involvement moNED: no evidence of disease.

Thirteen patients were assessed of the symptom of hematuria during thetreatment. Four patients had a medical history of hematuria (includingchronic hematuria, frank hematuria, occasional hematuria, or recurrentgross hematuria) had none or rare hematuria since Day 0. Patient #1(previously with chronic hematuria), 5 (previously with occasionalhematuria) and 9 (previously with recurrent gross hematuria) had nohematuria since Day 0. Especially, patient #1 had no hematuria for over200 days.

TABLE 2 Day Day Day Day Day Day Day Day Day Patent Age Med Hx 0 21 42 6384 120 150 180 201 1 96 Chronic Hematuria 0 0 0 0 0 0 0 0 0 2 85 FrankHematuria 0 0 0 0 1 ND 0 DC DC 3 98 None 0 0 0 0 0 0 DC DC DC 4 80 None0 0 0 0 0 TBD TBD TBD TBD 5 83 Occasional Hematuria 0 0 0 0 0 TBD TBDTBD TBD 6 84 None 0 1 0 1 0 TBD TBD TBD TBD 7 72 None 1 1 ND ND ND NDTBD TBD TBD 8 50 None 0 0 0 0 TBD TBD TBD TBD TBD 9 84 recurrent gross 00 0 TBD TBD TBD TBD TBD TBD hematuria 10 77 None 0 0 TBD TBD TBD TBD TBDTBD 11 88 None 0 0 TBD TBD TBD TBD TBD 12 84 None TBD TBD TBD TBD TBDTBD 13 86 None 0 TBD TBD TBD TBD TBD TBD TBD *TBD: to be determined; DC:discontinued; ND: not determined.

1-29. (canceled)
 30. A method of treating bladder cancer in anindividual comprising i) a first phase comprising administering about225 mg of gemcitabine locally to the bladder over at least one weekduring a first phase gemcitabine delivery period, ii) a rest period ofat least one month, iii) a maintenance phase comprising at least twomaintenance phase delivery periods, each comprising administering about225 mg of gemcitabine locally to the bladder over at least one week,wherein the maintenance phase delivery periods are separated by at leastone month.
 31. The method of claim 30, wherein the maintenance phasegemcitabine delivery periods are each 3 weeks.
 32. The method of claim30, wherein the gemcitabine is delivered by an intravesicular device inthe maintenance phase delivery periods.
 33. The method of claim 30,wherein the concentration of gemcitabine in the urine is from about 1μg/mL to about 10 μg/mL for at least one week during the maintenancephase delivery periods.
 34. The method of claim 30, wherein themaintenance therapy comprises delivering gemcitabine locally to thebladder of the individual every three months.
 35. The method of claim30, wherein the maintenance phase delivery periods are each three weeks.36. The method of claim 30, wherein the first phase comprises two ormore consecutive first phase gemcitabine delivery periods.
 37. Themethod of claim 36, wherein each first phase gemcitabine delivery periodis three weeks.
 38. The method of claim 30, wherein the individual isineligible for or has refused cisplatin-based chemotherapy.
 39. Themethod of claim 30, wherein the individual is unfit for, ineligible foror has refused a radical cystectomy.
 40. The method of claim 30, whereinthe individual has muscle invasive bladder cancer.
 41. The method ofclaim 40, wherein the individual has cT2, cT3, T3, or T4a muscleinvasive bladder cancer.
 42. The method of claim 30, wherein theindividual has non-muscle invasive bladder cancer.
 43. A method ofproviding maintenance therapy for an individual with bladder cancer,wherein the maintenance therapy follows at least one previous therapy,wherein the previous therapy comprises delivering gemcitabine locally tothe bladder of the individual continuously for at least one week,wherein the maintenance therapy comprises administering gemcitabinecontinuously to the individual two or more times during two or moremaintenance phase delivery periods wherein the gemcitabine is deliveredlocally to the bladder of the individual during the maintenance deliveryperiods, wherein each maintenance phase delivery period is at least oneweek, and wherein there is a rest period between each maintenance phasedelivery period of at least one month.
 44. The method of claim 43,wherein the gemcitabine is delivered at a dose from about 1 mg/day toabout 300 mg/day during the maintenance phase delivery periods.
 45. Themethod of claim 43, wherein 225 mg of gemcitabine is administered duringeach maintenance phase delivery period.
 46. The method of claim 45,wherein the gemcitabine is delivered by an intravesicular device. 47.The method of claim 43, wherein the concentration of gemcitabine in theurine is from about 1 μg/mL to about 10 μg/mL for at least one weekduring the maintenance phase delivery periods.
 48. The method of claim43, wherein the maintenance therapy comprises delivering gemcitabinelocally to the bladder of the individual every three months.
 49. Themethod of claim 43, wherein the previous therapy comprises two or moreconsecutive first phase gemcitabine delivery periods.
 50. The method ofclaim 49, wherein each first phase gemcitabine delivery period is aboutthree weeks.
 51. The method of claim 50, wherein the 225 mg ofgemcitabine is administered to the individual during each first phasegemcitabine delivery period.
 52. The method of claim 51, wherein thegemcitabine is delivered by an intravesicular device during each firstphase gemcitabine delivery period.
 53. The method of claim 43, whereinthe individual is ineligible for or has refused cisplatin-basedchemotherapy.
 54. The method of claim 43, wherein the individual isunfit for, ineligible for or has refused a radical cystectomy.
 55. Themethod of claim 43, wherein the individual has muscle invasive bladdercancer.
 56. The method of claim 43, wherein the individual has cT2, cT3,T3, or T4a muscle invasive bladder cancer.
 57. The method of claim 43,wherein the individual has non-muscle invasive bladder cancer.